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1
Jones, Christopher M. « Expression and folding studies of the ankyrin repeat domain of the capsaicin receptor ». Click here for download, 2006. http://wwwlib.umi.com/cr/villanova/fullcit?p1432833.
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FENG, LIN. « MODULATION OF SYNAPTIC TRANSMISSION AT THE NUCLEUS TRACTUS SOLITARIUS ». OpenSIUC, 2014. https://opensiuc.lib.siu.edu/dissertations/816.
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The caudal nucleus tractus solitarius (cNTS) is the key recipient of the primary afferents from visceral sensory neurons and also an important site that processes and integrates gastrointestinal, cardiovascular and respiratory functions. Glutamate and gamma-aminobutyric acid are the major neurotransmitters within the NTS, but studies have suggested that nicotinic acetylcholine receptors (nAChRs) and transient receptor potential (TRP) channels can modulate excitatory/inhibitory neurotransmission. I have designed studies to understand the role of nAChRs and TRP channels in the modulation of neurotransmission in the cNTS. In the first aim, experiments were designed to test the hypothesis that the cNTS contains function-specific subsets of neurons whose responsiveness to nicotine correlates with the target of their axonal projections. cNTS neurons send axonal projections to brain regions such as parabrachial nucleus (PBN), hypothalamic paraventricular nucleus (PVN), nucleus ambiguous (NA), dorsal motor nucleus of the vagus (DMV) and the caudal ventrolateral medulla (CVLM) and are involved in integrating autonomic and neuroendocrine functions. Presynaptic/postsynaptic modulation by nAChRs differ in the axonal projections of cNTS neurons, studying of which would provide better understanding of this complex integration. In vivo fluorescent tracing combined with in vitro slice patch-clamp electrophysiological recordings from anatomically identified caudal NTS neurons were used to study the expression and function of nAChRs (mainly á3â4 containing nAChRs) in the cNTS. Results from these studies demonstrate that presynaptic and postsynaptic responsiveness of caudal NTS neurons to nicotine correlates with the areas the neurons project to in the following order of prevalence: DMV>PVN>NA>CVLM>PBN (for presynaptic responses) and DMV>CVLM>PBN>NA>PVN (for postsynaptic responses). In the second aim, experiments were designed to test the hypothesis that nociceptive TRP channels TRPV1 (vanilloid) and TRPA1 (ankyrin) modulate synaptic transmission in the NTS. As a result of this modulation, the efferent functions that control autonomic and visceral functions will be regulated and account for the changes in autonomic neuropathy as patients with diabetes develop significant alterations in blood pressure and heart rate as well as silent myocardial ischemia as a result of blunted pain carrying ability. Results obtained from these studies demonstrated that TRPV1 and TRPA1 mRNA were detected in the dorsal root ganglion (DRG), but not in the NTS. Immunofluorescence studies revealed that TRPV1 and TRPA1 were expressed in the solitary tract central sensory terminals inputs to NTS but not in NTS neurons. This suggests that TRPV1 and TRPA1 are expressed only in solitary tract. Administration of capsaicin (TRPV1 agonist) and allyl isothiocyanate (AITC, TRPA1 agonist) both increased the frequency of s/mEPSCs without affecting spontaneous and miniature inhibitory postsynaptic currents (s/mIPSCs). Next, the modulation of TRPV1- and TRPA1-induced responses by utilizing a PKC activator (PDBu) was examined. Incubation of slices with PDBu synergistically increased the mEPSC frequency following capsaicin application suggesting an increased receptor affinity; however following application of AITC there was no significant change, suggesting that activation by covalent modification does not enhance binding affinity. Finally, the specificity of TRPV1 and TRPA1 effect on synaptic transmission by ablating TRPV1 and TRPA1were tested. There was no modulation of synaptic transmission in these animals, further confirming that capsaicin- and AITC-mediated modulation of synaptic transmission are specifically mediated by TRPV1 and TRPA1, respectively. Furthermore, animals with painful diabetic peripheral neuropthy exhibited enhanced synaptic activity at the NTS, suggesting a role in nociception and other visceral functions. In summary, nAChRs, TRPV1 and TRPA1 are expressed in the NTS and activation of which modulate excitatory synaptic transmission. The results obtained from these studies and their interpretation may provide a better understanding of the central mechanism of modulation on efferent functions from NTS that regulate cardiovascular, respiratory and gastrointestinal functions.
3
D'Acunto, Mariantonietta. « Total synthesis of terpenoidic unsatured dialdehydes and evaluation of their activity towards TRP receptors ». Doctoral thesis, Universita degli studi di Salerno, 2012. http://hdl.handle.net/10556/1764.
Texte intégralRésumé :
2010 - 2011The aim of this PhD project has been to develop new synthetic strategies in enantioselective preparation of natural products. In particular my attention has been focused on preparation of some natural metabolite, containing an α,β-unsaturated dialdehyde in a polycyclic backbone, and their synthetic analogue, in order to better understand structure activity relationship towards TRP receptors ion channels. The recent discover of the new thermoreceptor TRPA1 and given that these natural metabolites show also a widespread of bioactivities, such as antiproliferative and cytotoxic activity, has increased our interest towards these target ever more. Our purpose is to assay the bioactivity of synthesized products both as TRP receptor agonists and as antiproliferative compounds . The first chapter of this work is an introduction to these terpenoidic molecules, with a wide range of described natural occurring metabolite and their classification in drimane, isocopalane, and scalarane dialdehydes. Thus, the structure of TRP receptor is described with a brief history of these ion channels, starting from the first cloned receptor , the TRPV1 vanilloid. In the chapter 2 total syntheses of polygodial derivatives, both C-1 and C-3 functionalised, are described. Polygodial and C-1 functionalised drimanes have been prepared with an approach whose key step is a Diels Alder reaction; Drimane C-3 functionalised have been prepared with a radical chemistry approach... [edited by author]
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4
Stein, Marco Robert Philip. « Optochemical control of GABA(A) receptors and TRP channels and studies toward light-dependent regulation of NaV and mGluR6 ». Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-181106.
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5
Colton, Craig K. « TRPV3 is a polymodal receptor ». Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1164046830.
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6
Stein, Marco Robert Philip [Verfasser], et Dirk [Akademischer Betreuer] Trauner. « Optochemical control of GABA(A) receptors and TRP channels and studies toward light-dependent regulation of NaV and mGluR6 / Marco Robert Philip Stein. Betreuer : Dirk Trauner ». München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://d-nb.info/1069278661/34.
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7
Kim, Ju Young. « M1 muscarinic acetylcholine receptor regulation of endogenous transient receptor potential-canonical, subtype 6 (TRPC6) channels ». Connect to resource, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1117570788.
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Thesis (Ph. D.)--Ohio State University, 2005.Title from first page of PDF file. Document formatted into pages; contains xviii, 178 p.; also includes graphics. Includes bibliographical references (p. 163-178). Available online via OhioLINK's ETD Center
8
Cao, De-Shou. « Role of transient receptor potential (TRP) channels in nociception / ». Available to subscribers only, 2009. http://proquest.umi.com/pqdweb?did=1967913291&sid=2&Fmt=2&clientId=1509&RQT=309&VName=PQD.
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9
Cao, Deshou. « Role of Transient Receptor Potential (TRP) Channels in Nociception ». OpenSIUC, 2009. https://opensiuc.lib.siu.edu/dissertations/71.
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Transient receptor potential (TRP) channels play an important role in sensory and nonsensory functions. TRPVanilloid 1 and TRPVanilloid 4 are proposed to be involved in inflammation-induced pain. TRPV1 is extensively studied and it is specifically involved in inflammatory thermal hypersensitivity. Mechanical hypersensitivity is one of the significant components of nociception. Several receptors have been proposed to underlie mechanosensation. The molecular entities responsible for mechanosensation are not fully understood. In this study, I have characterized the properties of TRPV4, a putative mechanosensitive ion channel expressed in dorsal root ganglion (DRG) neurons and nonsensory tissues. First, I have investigated the expression and function of TRPV4 and TRPV1 in the DRG neuronal cell bodies as well as their central terminals and determined the modulation by protein kinase C (PKC). Both TRPV4 and TRPV1 are expressed in DRG and laminae I and II of the spinal dorsal horn (DH). Ca2+ fluorescence imaging and whole-cell patch-clamp experiments showed that both capsaicin-induced TRPV1 response and 4alpha-phorbol 12, 13-didecanoate (4alpha-PDD)-induced TRPV4 response were observed in a proportion of the same DRG neurons, suggesting their co-expression. Incubation of DRG neurons with phorbol 12, 13-dibutyrate (PDBu), a PKC activator, resulted in a significantly greater potentiation of TRPV4 currents than TRPV1 currents. In HEK cells heterologously expressing TRPV4, PDBu potentiated TRPV4-mediated single-channel current activity. In patch-clamped DH neurons, the application of 4alpha-PDD at the first sensory synapse increased the frequency but not the amplitude of the miniature excitatory postsynaptic currents (mEPSCs), suggesting a presynaptic locus of action. 4alpha-PDD-induced increase in the frequency of mEPSC was further facilitated by PDBu. These results suggest that TRPV4 in the central terminals modulates synaptic transmission and is regulated by PKC. Second, I have studied the mechanosensitivity of TRPV4 in cell-attached patches by applying direct mechanical force via the patch pipette. In TRPV4 expressing HEK cells, the application of negative pressure evoked single-channel current activity in a reversible manner and the channel activity was enhanced after incubation with PDBu. TRPV4 has been shown to be activated by hypotonicity. Here I show that negative pressure exaggerated hypotonicity-induced single-channel current activity. However, in similar experimental conditions, cells expressing TRPV1 did not respond to mechanical force. TRP channels are also expressed in non-sensory regions and the role of these channels is not fully understood. Both TRPV4 and TRPV1 are expressed in the hippocampus. Using whole-cell patch-clamp techniques, I have found that 4alpha-PDD increased the frequency, but not the amplitude of mEPSCs in cultured hippocampal neurons, suggesting a presynaptic site of action. Interestingly, the application of capsaicin had no effect on synaptic transmission in hippocampal neuronal cultures. Finally, I have investigated the expression and function of TRP channels in diabetes because TRP channels have been shown to be involved in peripheral neuropathy as well as vascular complications in diabetes. ROS production plays a critical role in the progress of diabetes. I propose that lower levels of ROS up-regulate the expression TRP channels in the early stages of diabetes, leading to hyperalgesia, and higher levels of ROS or chronic exposure to ROS down-regulate TRP channels in the late stages of diabetes, resulting in hypoalgesia. I have found that the expression of TRPV1 and phospho p38 (p-p38) MAPK was increased in DRG of streptozotocin (STZ)-injected diabetic and non-diabetic hyperalgesic mice. An increase in TRPV1 and p-p38 MAPK levels was induced by STZ or H2O2 treatment in stably TRPV1 expressing HEK cells, suggesting the involvement of STZ-ROS-p38MAPK pathway. TRPV4 has been reported to be involved in vasodilatation by shear stress in blood vessels. Here, I have demonstrated that TRPV4 is expressed in lymphatic endothelial cells (LECs). Treatment with low concentration of H2O2 enhanced the expression of TRPV4 at mRNA and protein levels in LECs, suggesting that mild levels of ROS up-regulate TRPV4 expression. In diabetes, beta cell dysfunction is responsible for decreased insulin release. TRPV4 is expressed in RINm5F (beta cell line), islets and pancreas. It has been shown that hypotonicity induced insulin release in beta cell lines, which was mediated by activation of stretch-activated channels, raising the possibility of the involvement of TRPV4, a mechanosensitive channel. Therefore, I have studied the functional role of TRPV4 in beta cells. Incubation with 4alpha-PDD enhanced insulin release in RINm5F cells, suggesting TRPV4 regulates insulin secretion from pancreatic beta cells. Since TRPV4 expression levels are decreased in diabetes, insulin secretion from beta cells may be impaired. In summary, TRPV1, a thermosensitive channel, and TRPV4, a mechanosensitive channel, contribute to thermal and mechanical hyperalgesia, respectively in the early stage of DPN through their up-regulation by ROS-p38 MAPK and insulin/IGF-1 pathways. Due to the mechanical sensitivity of TRPV4 channel, the up-regulation in the early stage and down-regulation in the late stage may be involved in the development of vascular complications and regulation of insulin release in diabetes.
10
Che, Hui, et 車慧. « Functional transient receptor potential channels in human preadipocytes and cardiac c-kit⁺ progenitor cells ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/196436.
Texte intégralRésumé :
Transient receptor potential (TRP) channels play important roles in cellular physiology and biology. The present PhD project investigated the functional expression of TRPV and TRPM channels in human preadipocytes and cardiac c-kit+ progenitor cells and their roles in regulating cell proliferation, adipogenic differentiation or migration. In addition, the role of store-operated Ca2+ entry (SOCE) channels in regulating cell proliferation and migration was also studied in human cardiac c-kit+ progenitor cells using multiple approaches including whole-cell patch voltage-clamp, confocal microscope, molecular biology, etc.
We found that TRPV2, TRPV4 and TRPM7 channels were abundantly expressed in human preadipocytes. Activation of TRPV2 channels by probenecid caused a long-lasting intracellular Ca2+ transient, while activation of TRPV4 channels by 4-PDD induced Ca2+ oscillations. TRPM7 current was recorded with a Mg2+-free pipette solution, and inhibited by 2-aminoethyl diphenyl borate (2-APB). Silence of TRPV2 or TRPM7, but not TRPV4, with the specific shRNA, reduced cell proliferation via inhibiting cyclin D1, cyclin E, and p-ERK1/2. Individually silencing these three channels decreased adipogenic differentiation by reducing p-Akt kinase. The results indicate that TRPV2, TRPV4 and TRPM7 are involved in adipogenesis, while TRPV2 and TRPM7, but not TRPV4, regulate cell proliferation in human preadipocytes.
In second part of the thesis, abundant expression of TRPV2, TRPV4, and TRPM7 channels was demonstrated in human cardiac c-kit+ progenitor cells. Similar to human preadipocytes, probenecid and 4-PDD activated Ca2+ signaling, and TRPM7 current recorded with a Mg2+-free pipette solution was inhibited by 2-APB. Silencing TRPV2 or TRPM7, but not TRPV4, inhibited cell proliferation by arresting cells at G0/G1 phase with a reduced cyclin D, cyclin E, and p-ERK1/2. Cell migration was decreased with silence of TRPV2, TRV4 or TRPM7 via inhibiting p-Akt kinase. The results show that TRPV2, TRPV4 and TRPM7 mediate cell migration, while TRPV2 and TRPM7, but not TRPV4 channels, participate in regulating cell proliferation.
In third part of the thesis, we demonstrated that SOCE channels were composed of TRPC1, STIM1 and Orai1 by protein-protein interaction. Silence of TRPC1, STIM1, or Orai1 with specific siRNA reduced Ca2+ influx through SOCE channels, decreased cell proliferation by inhibiting cyclin D1 and cyclin E, and slowed down cell migration via reducing p-Akt kinase. These results suggest that TRPC1, STIM1 and Orai1 are the major components of SOCE channels in human cardiac c-kit+ cells. SOCE channels play an essential role in regulating cell proliferation and migration.
Collectively, this PhD project has demonstrated for the first time that 1) TRPV2, TRPV4, and TRPM7 are abundantly expressed in human preadipocytes and cardiac c-kit+ progenitor cells. 2) These TRP channels regulate adipogenic differentiation in preadipocytes and migration in cardiac c-kit+ progenitor cells. 3) TRPV2 and TRPM7, but not TRPV4, are involved in cell proliferation of human preadipocytes and cardiac c-kit+ progenitor cells. 4) TRPC1, STIM1 and Orai1 are interacted to form SOCE channels and regulate cell proliferation and migration in human cardiac c-kit+ cells. 5) All the above physiological roles of TRPV2, TRPV4, TRPM7, and SOCE channels are mediated by cyclin D1, cyclin E, p-ERK1/2, and/or p-Akt.published_or_final_version
Medicine
Doctoral
Doctor of Philosophy
11
Bonsignore, Fulvio. « The fast diffusing p75NTR monomer : new perspectives for the neurotrophin signaling paradigm ». Doctoral thesis, Scuola Normale Superiore, 2019. http://hdl.handle.net/11384/85911.
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Takahashi, Nobuaki. « TRP channels as sensors of cellular redox status ». 京都大学 (Kyoto University), 2010. http://hdl.handle.net/2433/131892.
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13
Sengupta, Sukanya. « Understanding the mechanisms of retinal degeneration in Drosophila lacking transient receptor potential channels ». Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609679.
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Walker, Rebecca L. « Functional and molecular characterization of TRP channels in smooth muscle / ». abstract and full text PDF (UNR users only), 2002. http://0-gateway.proquest.com.innopac.library.unr.edu/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3068507.
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15
Wang, Qian, et 王倩. « Mechanistic study of the transient receptor potential melastain 2 (TRPM2)-Ca²⁺ signaling in ROS induced switch between apoptosis and autophagy ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/206750.
Texte intégralRésumé :
Autophagy is a major catabolic pathway for maintaining cell homeostasis through degradation and recycle of macromolecules and organelles. Autophagy can be activated under environmental stress conditions, including reactive oxygen species (ROS). TRPM2, a non-selective trans-membrane calcium channel, can be activated by ROS that, in turn, leads to intracellular 〖Ca〗^(2+) increase through 〖Ca〗^(2+) influx. It is well known that ROS regulates autophagy, and vice versa. Yet, the molecular mechanisms underlying the interplay between ROS and autophagy remain elusive. Here we studied the role of TRPM2-mediated 〖Ca〗^(2+) influx in interplay between ROS and autophagy.
From our study, we found that ROS activated TRPM2 for 〖Ca〗^(2+) influx via ADPR to inhibit early autophagy induction, which ultimately led to apoptosis in TRPM2 expressing cancer cell lines. On the other hand, ROS induced autophagy, not apoptosis, for cell survival in cancer cell lines which do not express TRPM2, and autophagy inhibition, either by ATG5 knockdown or by treating cells with bafilomycin A1 (an autophagy inhibitor), converted cells to apoptosis upon ROS treatment. In addition, ROS dramatically changed mitochondrial morphology, increased mitochondrial 〖Ca〗^(2+) content, and abolished mitochondrial membrane potential in TRPM2 expressing cells. Moreover, we found that ROS-induced Ca2+ influx via TRPM2 actually activated calmodulin-dependent protein kinase II (CaMKII) to phosphorylate Ser295 on Beclin1. Phosphorylated Beclin1, in turn, decreased the association between Beclin1 and VPS34, but induced the binding between Beclin1 and BCL-2. In summary, our data demonstrated that the TRPM2/〖Ca〗^(2+)/CaMKII/ Beclin1 cascade is the molecular switch between autophagy and apoptosis in response to ROS. Since dysregulation of ROS and autophagy has been associated with a variety of human diseases, e.g. cancer, neurological disorders, heart diseases, and liver diseases, manipulating the TRPM2/〖Ca〗^(2+)/CaMKII/ Beclin1 cascade should provide novel treatment option for these diseases.published_or_final_version
Physiology
Doctoral
Doctor of Philosophy
16
Bernardini, Michela. « Transient receptor potential (TRP) channel role in prostate cancer invasion and angiogenesis regulation ». Thesis, Lille 1, 2015. http://www.theses.fr/2015LIL10157/document.
Texte intégralRésumé :
Le cancer de la prostate (CaP) représente la deuxième cause de mortalité par cancer dans les pays développés. L'invasion des tissus environnants et l'angiogenèse tumorale promeut la métastase de CaP vers des organes éloignés. L’expression de plusieurs canaux TRP (Transient Receptor Potential) est dérégulée dans les cellules cancéreuses et les cellules endothéliales (CE) dérivées de tumeurs. Ils ont donc été proposés comme marqueurs pour la progression du cancer ainsi que comme cibles potentielles pour une thérapie pharmaceutique. Afin d'étudier les canaux TRP dans la vascularisation du CaP, nous avons isolé et caractérisé trois lignées de CE derivées du CaP (PTEC). Nous avons testé sur les PTEC l'effet de deux molécules anti-angiogénique en combinaison avec des médicaments anti-androgèniques. Les résultats démontrent un comportement résistant des PTEC à des médicaments anti-angiogéniques par rapport à des CE normales. Nous avons criblé l'expression de tous les canaux TRP dans les CE saines et celles dérivées de trois types tumoraux (prostate, sein, rein). Nous avons identifié cinq candidats ‘spécifiques’ du CaP dérégulés seulement dans les PTEC qui ont été caractérisés au niveau fonctionnel et leur rôle potentiel en tant que modulateurs de l'angiogenèse in vitro a été testé. En outre, nous avons étudié le rôle inhibiteur de TRPM8 dans la migration des cellules cancéreuses prostatiques CaP et nous avons également détecté TRPM8 dans les CE dans lesquelles nous avons observé aussi un rôle anti migratoire de TRPM8. Pris dans leur ensemble, nos résultats mettent en lumière de nouveaux acteurs moléculaires pour cibler sélectivement la progression du CaP et son angiogenèseProstate cancer (PCa) is the second most lethal male tumor in developed countries. Metastasis to distant organs is mainly mediated by tissue invasion and angiogenesis, which are indeed two of the main cancer hallmarks. Several Transient Receptor Potential (TRP) proteins are deregulated in cancer cells and angiogenesis and have been suggested as valuable markers in predicting cancer progress and as potential targets for pharmaceutical therapy. In order to screen and study TRP channels in PCa vasculature, we isolated and characterized three lines of human endothelial cells (ECs) from PCa patients (PTEC). We tested the effect of two anti-angiogenic in combination with anti-androgen drugs. The results clearly demonstrate a resistant behavior of endothelial cells isolated from prostate cancer to specific anti-angiogenic drugs compared to normal endothelial cells. We fully profiled the expression of TRP channels in tumor (prostate, breast and renal) and healthy ECs, with particular interest for prostate tumor EC. We identified five ‘prostate specific’ candidates deregulated in PTEC compared to endothelial derived from healthy prostate. ‘Prostate specific’ TRP candidates were functionally characterized and their potential role as in vitro angiogenesis modulators investigated. Our laboratory has already extensively studied the role of TRPM8 in PCa progression and migration. For this reason, we further investigated the molecular mechanism underling this effect in PCa cells as well as in ECs. Taken together, our results bring to light TRP channels as novel molecular players to selectively target prostate tumor progression and angiogenesis
17
Silva, Cássia Regina da. « ENVOLVIMENTO DO RECEPTOR TRPA1 NA RESPOSTA INFLAMATÓRIA INDUZIDA PELA ADMINISTRAÇÃO TÓPICA DE CINAMALDEÍDO EM CAMUNDONGOS ». Universidade Federal de Santa Maria, 2011. http://repositorio.ufsm.br/handle/1/11180.
Texte intégralRésumé :
Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorCinnamaldehyde, a natural compound frequently present in cosmetic formulations, induces skin irritation when topically applied, but the mechanism by which cinnamaldehyde produces such skin reactions is unclear. Here, we showed that cinnamaldehyde induced ear edema in mice (1-6 μg/ear) with a maximum effect with 4 μg/ear (Emax of 0.18 ± 0.02 mm and an ED50 value of 2.0 (1.1- 3.4 μg/ear). Cinnamaldehyde can induce leukocyte infiltration detected by an increase in MPO activity and confirmed by histological analyses. The edema and cellular infiltration evoked by 4 μg/ear of cinnamaldehyde was prevented through topical application of ruthenium red, a non selective TRP antagonist or by camphor and HC030031, two TRPA1 receptor antagonists. In contrast, the edema and the leukocyte infiltration was unaffected by the TRPV1 receptor antagonist SB366791. Cinnamaldehydeinduced edema but not cellular infiltration was also prevented though topical application of the tachykinin NK1 antagonist aprepitant, indicating a neuropeptides release phenomenon in this process. Also, we observed that repeated topical applications of cinnamaldehyde (4 μg/ear) did not induced sensitization/desensitization alterations. Interestingly, the TRPV1 antagonist, capsaicin, repeated treatment abrogated its edematogenic response, confirming the desensitization process and decrease partially the cinnamaldehyde induced edema, suggesting the involvement of capsaicin-sensitive fibers and additional targets in cinnamaldehyde response. The present results demonstrated that cinnamaldehyde induces mouse skin inflammation through a mechanism involved the TRPA1 receptor activation and subsequent leukocyte infiltration. In addition, evidence supports the assumption that the tachykinin NK1 receptor is involved in these inflammatory responses.
O cinamaldeído é um composto natural frequentemente encontrado em formulações cosméticas, capaz de induzir irritação na pele quando aplicado topicamente, porém o mecanismo pelo qual o cinamaldeído produz estas reações ainda é desconhecido. Neste trabalho demonstramos que o cinamaldeído foi capaz de induzir edema de orelha em camundongos (1-6 μg/orelha) com um efeito máximo obtido com a dose de 4 μg/orelha (Emax de 0,18 ± 0,02 mm e um DE50 de 2,0 (1,1- 3,4) μg/orelha). O cinamaldeído foi capaz ainda de induzir infiltração leucocitária detectada por um aumento na atividade da MPO e confirmada por análise histológica. O edema e a infiltração leucocitária iniciados após aplicação tópica de 4 μg/orelha de cinamaldeído foi prevenido pela aplicação tópica de vermelho de rutênio, um antagonista TRP não seletivo, e por cânfora e HC030031, dois antagonistas seletivos TRPA1. Por outro lado, a aplicação de SB366791, um antagonista seletivo TRPV1, não alterou o edema nem a infiltração leucocitária. Ainda, o edema induzido pelo cinamaldeído foi prevenido pela aplicação tópica de aprepitant, um antagonista seletivo do receptor NK1 para taquicininas, sugerindo que a liberação de neuropeptídeos esteja envolvida neste processo. Também foi observado que a aplicação tópica repetida de cinamaldeído 4 μg/orelha não foi capaz de induzir processos de ensibilização/dessensibilização. No entanto, o tratamento repetidocom o antagonista TRPV1, capsaicina, aboliu o edema induzido pela própria capsaicina, confirmando a ocorrência de dessensibilização, e diminuiu parcialmente o edema induzido pelo cinamaldeído sugerindo o envolvimento de fibras sensíveis a capsaicina, além de outras vias, neste processo. Os resultados demonstram que o cinamaldeído induz um processo inflamatório na pele através de um mecanismo que envolve a ativação do receptor TRPA1 e consequente infiltração leucocitária.
18
Baxter, Matthew. « The role of Transient Receptor Potential (TRP) channels in the pathogenesis of COPD ». Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/29840.
Texte intégralRésumé :
COPD is currently the 4th most prevalent cause of death worldwide. Despite the global impact, there are no currently available treatments which impede disease progression. This lack of effective therapies is largely due to an inadequate understanding of the mechanisms which drive disease progression. Cigarette smoke (CS), the most important risk factor for COPD, is thought to initiate an inflammatory response in the lungs which becomes self-propagating and dysregulated. Chronically, this inflammatory response drives structural and functional changes. The mechanisms by which CS elicits this inflammatory response, however, remain unclear. Certain CS constituents are known to activate Transient Receptor Potential (TRP) ion channels. A number of TRP channels are actively expressed in the lung tissue or inflammatory cells, and a further few are also implicated in the generation of inflammation. Owing to these features, it was hypothesised that TRP channels A1, C6, M2, M8, V1 and V4 have a role in CS-induced airway inflammation and, consequently, the pathogenesis of COPD. To test this hypothesis, three murine models of induced airway inflammation were characterised: acute CS, sub-chronic CS and endotoxin (LPS). Lung-tissue TRP channel expression levels were measured in these models alongside human lung-parenchyma samples from non-smokers, smokers and emphysema patients. Mice deficient for specific TRP channels were profiled in the CS-model and the LPS-model to establish the role of TRP channels in the initiation of inflammation in disease and non-disease settings. TRPV1-/-, TRPV4-/- and TRPM8-/- mice exhibited significantly reduced levels of airway inflammation compared to wild-types after acute CS, but normal responses to the innate (LPS) challenge. This data suggests that modulation of TRP channels could represent a novel anti-inflammatory approach for combating smoke induced diseases like COPD without impacting on the normal, essential innate defence mechanisms.
19
Arkenbout, Elisabeth Karin. « TR3 nuclear orphan receptor in cardiovascular disease ». [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2004. http://dare.uva.nl/document/77443.
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20
Davies, Todd Howard. « Regulation of glucocorticoid receptor function by associated TPR-domain proteins ». Connect to full-text via OhioLINK ETD Center, 2003. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=mco1098292002.
Texte intégralRésumé :
Thesis (Ph. D.)--Medical College of Ohio, 2003."In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Medical Sciences." Major advisor: Edwin Sanchez. Includes abstract. Document formatted into pages: iv, 126 p. Title from title page of PDF document. Includes bibliographical references (p. 100-124).
21
Peach, Megan L. « Molecular modeling of the bacterial chemotaxis receptors Tar and Trg / ». Thesis, Connect to this title online ; UW restricted, 2001. http://hdl.handle.net/1773/8123.
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Wong, Josée F. K. 1972. « Neurotrophins and Trk receptor signaling in cortical development ». Thesis, McGill University, 2000. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=33454.
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Neurotrophin-3 was reported to promote cell cycle exit and differentiation of cortical progenitors. We wanted to identify which signaling pathways are responsible for these changes. We observed that chronic treatment of progenitors with BDNF or NT-3, but not NGF resulted in changes in morphology, visualized by MAP2 staining. BDNF treatment led to an increase in primary neurites in calbindin- and calretinin-positive cells when compared with control, but had no effect on proliferation of the proportion of interneurons. We conclude that BDNF enhances the differentiation of cortical neurons. To investigate the role of Trk signaling in cortical neurons, we generated recombinant adenoviruses which carried either wild type or mutated forms of TrkA which inhibit binding and activation of some of its major downstream effectors, namely, SNT, SHC and PLCgamma. Future work should elucidate the role of Trk signaling in central nervous system using these vectors.
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Nagakura, Ikue. « Regulation of an Aplysia Trk-like receptor by serotonin and identification of serotonin G protein- coupled receptors that can activate protein kinase C Apl II ». Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:8881/R/?func=dbin-jump-full&object_id=92183.
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Curry, Haley Nicole. « Characterization of a Conserved Transient Receptor Potential Channel Supporting Spermatogenesis in Planarian Flatworms ». Wright State University / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=wright1589976835122505.
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Waddell, Trinity Q. « Role of Transient Receptor Potential Channels in Epithelial Morphogenesis in Chick Embryo ». BYU ScholarsArchive, 2019. https://scholarsarchive.byu.edu/etd/8112.
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Transient Receptor Potential channels (TRP) are a superfamily of cationic specific ionchannels that are regulated by various stimuli such as temperature, pH, mechanical stress, ligandsand ion concentration. The role of TRP channels in disease states such as autosomal dominantpolycystic kidney disease, cancer metastasis, and developmental defects lend credence to thebelief that they play an important part in epithelial morphogenesis events. The development ofsomites, neural tube closure and migration of neural crest cells to form things such as the faceand heart is a good developmental model for the aforementioned cellular processes. We haveshown that TRP channels can be found in the developing ectoderm, hindbrain, and heart and thatthe inhibition of TRP channels in a developing embryo results in phenotypes suggestingperturbation of cellular remodeling processes. This leads to the question of the specific role ofTRP channels in the epithelial mesenchymal transition and remodeling in developing chickembryos.
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Kamikura, Darren M. « Structurefunction analysis of the met receptor oncoprotein, Tpr-met ». Thesis, McGill University, 1999. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=37575.
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The Met protooncogene encodes a receptor tyrosine kinase that is deregulated by point mutation, and overexpression/amplification in a number of human tumours. The Met receptor is also oncogenically activated following genomic rearrangement which generates a cytoplasmic, constitutively activated fusion protein, Tpr-Met. In addition to autophosphorylation sites within the catalytic domain, the carboxy terminus of Tpr-Met/Met contains a single major site of autophosphorylation, tyrosine 489. This tyrosine residue represents a unique multisubstrate binding site, capable of binding numerous intracellular proteins, and is critical for the biological activities of both the Met receptor and Tpr-Met oncoprotein. Addition of the c-src myristoylation sequence to the amino terminus of the normally cytoplasmic Tpr-Met, localizes Tpr-Met to plasma membranes and enhances cellular transformation, in vitro invasion, and tumourigenicity. Furthermore, a membrane targetted Tpr-Met is localized to a similar subcellular compartment as the Met receptor, and alters the complement of signalling proteins required for efficient transformation. In this respect, a membrane localized Tpr-Met resembles oncogenic forms of the transmembrane Met receptor, and provides a model with which to study transformation by Met receptor oncoproteins. Significantly, membrane localization of Tpr-Met induces a phosphoinositide 3' kinase (PI3' K) dependent autocrine loop, involving the production of hyaluronic acid (HA), and post-translational modification of the cell surface receptor for HA, CD44. PI3'K activity and the HA/CD44 autocrine loop, are dependent on the multisubstrate binding site, tyrosine 489, and tyrosine residue 498, a residue with no previously described biochemical function. Although the exact mechanisms by which PI3'K regulates HA production are unclear, the induction of a HA/CD44 autocrine loop may represent a novel mechanism by which deregulated receptor tyrosine kinases increase their onco
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Davies, Todd Howard. « Regulation of Glucocorticoid Receptor Function by TPR-domain Proteins ». University of Toledo Health Science Campus / OhioLINK, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=mco1098292002.
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Amaral, Michelle Dawn. « TRP-ing down a TRK a new role for transient receptor potential channels as novel mediators of brain-derived neurotrophic factor actions at both sides of the excitatory synapse / ». Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2008. https://www.mhsl.uab.edu/dt/2008p/amaral.pdf.
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Almeida, Mônica Moura de. « Efeitos cardiovasculares induzidos pelo óleo essencial de mentha x-villosa hudson (oemv), rotundifolona e mentol em ratos espontaneamente hipertensos – o papel dos canais potencial receptor transiente (trp) ». Universidade Federal da Paraíba, 2015. http://tede.biblioteca.ufpb.br:8080/handle/tede/9496.
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
The monoterpenes found in essential oils from plants act on transient receptor potential channels (TRP). Some TRP channels with altered expression in hypertensive rats may be new therapeutic targets for the control of hypertension. Aim: Compare the responses induced by Essential Oil of Mentha x villosa Hudson (OEMV), rotundifolone and menthol in Spontaneously Hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY), evaluating the role of TRP channels. Methods and Results: In vivo (blood pressure measurement and heart rate), in vitro (measure of the frequency and force of contraction in the atria and the isometric tension in superior mesenteric arteries) and biochemical (PCR and Western blot) studies were used. The OEMV (3, 5, 10 and 20 mg/kg), the rotundifolone (10, 20 and 30 mg/kg) and the menthol (3, 5, 10 and 20 mg/kg) induced significant hypotensive and bradycardic response in non-anesthetized SHR and WKY rats. The reduction in the diastolic blood pressure was significantly greater than the decrease in the systolic blood pressure, suggesting a greater action on the vascular component of blood pressure. However, the significant bradycardic effect and reduction in the systolic blood pressure also suggest an action on the cardiac component. Furthermore, the decrease in the blood pressure and heart rate induced by rotundifolone and by menthol were significantly more potent in SHR. The action of OEMV, the rotundifolone and menthol in the right atrium (with spontaneous activity) and left (electrically stimulated) showed negative inotropic and chronotropic effects and culminating in complete inhibition of cardiac activity. Moreover, the negative inotropic effect was more potent in SHR and protein TRPM8 channel showed increased expression in the ventricles (left > right) and atria (left > right) of SHR rats. Also, OEMV, rotundifolone and menthol induced vasorelaxant response in superior mesenteric arteries of SHR and WKY rats, precontracted with PHE. The major mechanism involves the endothelium-independent route, which was more potent in SHR. The mechanism of the endothelium-independent vasorelaxant response induced by rotundifolone and menthol probably involves TRPM8 channels, which showed increased expression in SHR, and TRPC1, TRPC3 and TRPC6 channels. However, the response induced by menthol in WKY rats involves other TRP channels (probably TRPM6 and TRPM7). In addition, the flow cytometry showed an increase in [Ca2+]i induced by rotundifolone in SHR vascular myocytes, probably by activating of the TRPM8 channel. Conclusions: The hypotensive, bradycardia, negative inotropic and vasorelaxant responses induced by OEMV, rotundifolone and menthol were significantly more potent in SHR than in WKY rats. The mechanism of the endothelium-independent vasorelaxant response induced by rotundifolone and menthol involves TRPM8, TRPC (probably TRC1, TRPC3 and TRPC6), BKCa and CaV channels, but menthol may be acting in other TRP channels (probably TRPM6 and TRPM7) in WKY rats. The TRPM8 channel showed increased expression in SHR rats. Thus, the action of OEMV, rotundifolone and menthol on these channels can be related with the higher potency observed in SHR rats.
Os monoterpenos presentes em óleos essenciais de plantas atuam sobre canais Potencial Receptor Transiente (TRP). Alguns canais TRP com expressão alterada em ratos hipertensos podem ser novos alvos terapêuticos para o controle da hipertensão arterial. Objetivo: Comparar as respostas induzidas pelo Óleo Essencial de Mentha x-villosa Hudson (OEMV), pela rotundifolona e pelo mentol em Ratos Espontaneamente Hipertensos (SHR) e normotensos Wistar Kyoto (WKY), avaliando o papel de canais TRP. Métodos e Resultados: Estudos in vivo (medida de pressão arterial e freqüência cardíaca), in vitro (medida da freqüência e força de contração em átrios e da tensão isométrica em artérias mesentéricas superiores) e bioquímicos (PCR e Western blot) foram usados. O OEMV (3, 5, 10, 20 mg/kg), a rotundifolona (10, 20 e 30 mg/kg), e o mentol (3, 5, 10 e 20 mg/kg) induziram significativa resposta hipotensora e bradicárdica em ratos SHR e WKY não-anestesiados. A redução na pressão arterial diastólica foi significativamente maior do que a redução na pressão arterial sistólica, sugerindo uma maior ação sobre o componente vascular da pressão arterial. Entretanto, o significativo efeito bradicárdico e a redução na pressão arterial sistólica sugerem também uma ação sobre o componente cardíaco. Além disso, a diminuição na pressão arterial e freqüência cardíaca induzida por rotundifolona e por mentol foram significativamente mais potentes em ratos SHR. A ação do OEMV, da rotundifolona e do mentol em átrios direito (com atividade espontânea) e esquerdo (estimulado eletricamente) mostrou efeitos cronotrópico e inotrópico negativos e culminando na completa inibição da atividade cardíaca. Além disso, o efeito inotrópico negativo foi mais potente em ratos SHR e a proteína do canal TRPM8 mostrou expressão aumentada nos ventrículos (esquerdo > direito) e nos átrios (esquerdo > direito) de ratos SHR. O OEMV, a rotundifolona e o mentol também induziram resposta vasorrelaxante em artérias mesentéricas superiores de ratos SHR e WKY, pré-contraídos com FEN. O mecanismo majoritário envolve a via independente do endotélio, que foi mais potente em ratos SHR. O mecanismo da resposta vasorrelaxante independente do endotélio induzida por rotundifolona e mentol envolve provavelmente canais TRPM8, que apresentaram expressão aumentada em ratos SHR, e canais TRPC1, TRPC3 e TRPC6. Entretanto, a resposta induzida por mentol em ratos WKY envolve outros canais TRP (provavelmente TRPM6 e TRPM7). Além disso, a citometria de fluxo mostrou um aumento na [Ca2+]i induzido por rotundifolona em miócitos vasculares de ratos SHR, provavelmente por ativação de canais TRPM8. Conclusões: As respostas hipotensora, bradicárdica, inotrópica negativa e vasorrelaxante induzidas por OEMV, rotundifolona e mentol foram significativamente mais potentes em ratos SHR do que em ratos WKY. O mecanismo da resposta vasorrelaxante independente de endotélio induzida por rotundifolona e mentol envolve canais TRPM8, TRPC (provavelmente TRPC1, TRPC3 e TRPC6), BKCa e CaV, porém o mentol pode estar atuando em outros canais TRP (provavelmente TRPM6 e TRPM7) em ratos WKY. Os canais TRPM8 mostraram expressão aumentada em ratos SHR. Dessa forma, a ação do OEMV, da rotundifolona e do mentol sobre esses canais pode estar relacionada com a maior potência observada em ratos SHR.
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Kamikura, Darren M. « Structure/function analysis of the Met receptor oncoprotein, Tpr-Met ». Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0019/NQ55343.pdf.
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Reis, Milena Ramos. « Participação dos canais “Transient Receptor Potential - TRP” nos efeitos cardiovasculares induzidos por carvacrol em ratos com Hipertensão essencial ». Instituto de Ciências da Saúde, Universidade Federal da Bahia, 2015. http://repositorio.ufba.br/ri/handle/ri/20869.
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O carvacrol, um monoterpeno fenólico encontrado nos óleos essenciais de diversas plantas do gênero Origanum, já demonstrou causar hipotensão e vasodilatação em diferentes leitos vasculares de ratos normotensos, porém, seu efeito em ratos hipertensos ainda não foi elucidado. O objetivo deste estudo foi investigar os efeitos cardiovasculares do carvacrol em ratos espontaneamente hipertensos (SHR) e comparar com normotensos Wistar, utilizando ensaios farmacológicos in vitro (estudos funcionais e celulares) e in vivo. Nos ensaios funcionais in vitro, anéis de artéria mesentérica superior isolada de animais hipertensos e normotensos foram précontraídos com FEN (1μM) e o efeito de carvacrol (10-8-10-3M) foi observado. Em SHR, este monoterpeno induziu vasodilatação dependente de concentração (pD2=5,13 ± 0,05; Emáx=115,14 ± 5,46%; N=8) e, após a remoção do endotélio funcional, a potência da droga foi alterada significantemente (pD2=4,91 ± 0,05 N=9; p<0,01), sugerindo que a resposta vasodilatadora induzida por carvacrol, provavelmente, envolve uma via dependente e outra independente do endotélio vascular, porém, esta última parece ser a majoritária e, por isso, os ensaios seguintes foram realizados na ausência do endotélio vascular. Interessantemente, quando comparada com animais normotensos, a potência farmacológica de carvacrol foi reduzida significantemente (pD2=4,91 ± 0,05; N=9; p<0,05). Em anéis de ratos hipertensos, carvacrol reduziu o influxo de Ca2+ por canais Cav tipo-L, SOC e ROC, estes resultados foram semelhantes aos obtidos em ratos normotensos. Em ratos hipertensos, mas não em normotensos, a potência farmacológica do carvacrol em anéis pré-contraídos com FEN e na presença de diferentes inibidores de canais TRP (íon Gd3+, 10-5M; 2-APB, 10-6M ou 10-5M; BCTC, 2μM; 9-fenantrol, 10-5M; ou HC03003-1, 10-5M), foi reduzida em relação ao controle na ausência destes bloqueadores, sugerindo que os canais sensíveis à estes bloqueadores (TRPC1-7, TRPM2, M4 e TRPM8, TRPV1 e TRPA1), provavelmente, estão participando dos efeitos vasculares mediados por carvacrol e podem estar envolvidos no processo hipertensivo. Em estudos de patch-clamp em células de artéria mesentérica dispersas de ratos hipertensos, carvacrol (300μM) reduziu as correntes de entrada de Ba2+ por Cav tipo-L e este efeito foi semelhante em ratos normotensos. Além disso, em células de ratos hipertensos, o Mg2+ (2,5mM), bloqueador do TRPM6 e TRPM7, reduziu as densidades de ITRPM de entrada e saída, assim como carvacrol (100μM e 300μM), na ausência ou presença do 2-APB (100μM), bloqueador de TRPM7. A presença do 2-APB provocou inibição adicional nas densidades de ITRPM pelo carvacrol (100μM, mas não 300μM). Altas concentrações intracelulares de Mg2+ reduziram the magnitude of ITRPM7. Foi evidenciado que a ITRPM no controle é menor em ratos hipertensos que em normotensos. Estes dados obtidos e os relatados na literatura são sugestivos para provável inibição de ITRPM7 por carvacrol em células mesentéricas nativas. O efeito anti-hipertensivo do carvacrol foi avaliado por administração via orogástrica (50mg/kg/dia) durante 20 dias foi capaz de reduzir a pressão arterial média dos animais SHR tratados, no 20º dia do tratamento. O tratamento subcrônico com carvacrol não alterou os pesos cardíaco e corpóreo, nem a reatividade vascular. Em conclusão, esses dados sugerem que carvacrol possui atividade anti-hipertensiva em animais SHR, que pode ser devido ao seu efeito vasodilatador em anéis de artéria mesentérica superior isolada, provavelmente, por inibição do influxo de Ca2+ por Cav tipo-L, ROC, SOC e/ou canais TRPC1, 3 ou 6, além da inibição de correntes tipo-TRPM7 em miócitos mesentéricos.
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Andrade, Débora Cristiane da Silva. « Expressão do fator de crescimento neuronal (FCN), do seu receptor (trk A) e dos receptores de estrogênio e progesterona no peritôneo pélvico em mulheres com dor pélvica crônica ». Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/17/17145/tde-27092013-101243/.
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Dor pélvica crônica (DPC) afeta grande númerode mulheres e seu manejo ainda permanece complexo e insatisfatório. Estudos têm demonstrado um envolvimento do fator de crescimento neuronal (FCN) no processo de cronificação da dor. Participação hormonal neste processo também tem sido aventada, visto autores terem demonstrado influência estro/progestacional sobre nociceptores tanto direta quanto indiretamente através da influência exercida sobre os fatores neurotróficos. Foi objetivo deste estudo, verificar a associação entre a expressão do fator de crescimento neuronal (FCN), seu receptor (trk A) e os receptores de estrogênio e progesterona no peritôneo pélvico com a presença de dor pélvica crônica. Para tal foi realizado um estudo transversal incluindo um grupo de 22 mulheres com DPC, 8 com DPC e usuárias de anticoncepcional oral (DPC/ACO) e 7 sem dor. A dor foi analisada pela escala analógica visual (EAV) e questionário de McGill. Foi realizado imunohistoquímica para avaliar FCN e seu receptor trk A, receptores de estrogênio (RE) e progesterona (RP). A expressão de FCN teve media de 5, variando de 0 a 8, no grupo DPC, 5,5 no grupo DPC/ACO variando 3 a 8, e no grupo sem dor de 5 variando de 3 a 8 (p>0,05). A expressão de trk A apresentou media de 6, variandode 3 a 8, no grupo DPC, 6 no grupo DPC/ACO, variando de 4 a 8, e 6 no grupo sem dor variando de 4 a 6 (p>0,05). A expressão do RE apresentou média 4 no grupo DPC, variando de 0 a 8, 3,5 no grupo DPC/ACO variando de 0 a 8, e 7 no grupo sem dor, variando de 6 a 8 (p<0,05). A expressão do RP teve média 6,5 no grupo DPC, variando de 0 a 8, 5 no grupo DPC/ACO, variando de 0 a 7, e 7 no grupo sem dor, variando de 5 a 8 (p>0,05). Nossos resultados sugerem um papel anti-nociceptivo do estrogênio no peritôneo pélvico de mulheres no menacme, não mediado por expressão de FCN ou trk A.Chronic pelvic pain (CPP) affects a great number of women and its management still remains complex and unsatisfactory. Studies have shown an involvement of the neuronal growing factor (NGF) in the process of permanence of pain. Hormonal participation in this process has also been put forward, as some authors have demonstrated estro/progestational influence under nociceptors direct or indirectly through their influence on neurotrofic factors. This study aimed to verify the association among the expression of neuronal growing factor (NGF), its receptor (TrKA) and the estrogen and progesterone receptors in the pelvic peritoneum with the presence of chronic pelvic pain. A transversal study was carried out including a group of 22 women with CPP, 8 with CPP and users of oral anticonceptional (CPP/OAC) and 7 without pain. The pain was analized by the visual analogic scale (VAS) and McGill\'s questionnaire. Imunehistochemical was performed to evaluate the NGF and its receptor TrKA, estrogen (ER) and progesteron (PR) receptors. The expression of NGF was an average of 5, varying from 0 to 8, in group CPP, 5,5 in group CPP/ OAC varying from 3 to 8, and in the group without pain varying from 3 to 8 (p>0,05). The expression of TrKA presented an average of 6, varying from 3 to 8, in the group CPP, 6 in the group CPP/OAC, varying from 4 to 8, and 6 in the group without pain varying from 4 to 6 (p>0,05). The expression of ER presented an average of 4 in the group CPP, varying from 0 to 8, 3,5 in group CPP/OAC varying from 0 to 8, and 7 in group without pain, varying from 6 to 8 (p<0,05). The expression of PR had an average 6,5 in the group CPP, varying from 0 to 8,5 in the group CPP/OAC, varying from 0 to 7, and 7 in the group without pain, varying from 5 to 8 (p>0,05). Our studies suggest an anti- nociceptive rule of estrogen in the pelvic peritoneum of women in menacme, not mediated by expression of NGF or TrKA.
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Luxemburg, Michael. « Computational Modeling and Characterization of the Human Tri-Heteromeric GABAA Receptor ». Thesis, KTH, Tillämpad fysik, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-256348.
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-aminobutyric acid receptors of type A (GABAARs) are the majorinhibitory neurotransmitter receptors in the human brain, andare modulated by a vast range of exogenous molecules, such assedatives and anesthetics. In the last year, the first cryo-electronmicroscopy (cryo-EM) images of the closed and desensitized statesof the GABAAR were released, enabling fruitful research throughsimulations of these complex proteins. This report investigatesthe characteristics of the two structures. Specifically, pore hydration,radius, and hydrophobicity is compared, and a major focuslies in the general anesthetic (GA) binding pockets in the transmembranedomain, as well as the ligands propofol, etomidate,and pentobarbital. Furthermore, different models for the missingstructure of the intracellular domain (ICD) are compared. Thestructures were simulated for 1 μs using GROMACS. Using multiplesequence alignment as the basis of different models with theheptapeptid SQPARAA in the place of the ICD, resulted in stablestructures with a backbone RMSD close to 2 Å after 1 μs. Thepores are shown to exhibit significant differences between the twostates, with heavier constriction at the 9’ site of the closed state,but also suspected faulty expansion of the pore near the top in thedesensitized state after equilibration. Two of the pockets in thedesensitized state further deviates from expectation, by being tooconstricted. The other pockets were large enough to bind ligandsin the desensitized state, but not in the closed state, as expected.The binding analysis of the GAs suggests that etomidate bindswith the phenyl ring pointing towards the ICD, and that pentobarbitalbinds with the head group pointing towards the pore. Italso suggests that the GAs can bind to every GA pocket, but thatmodulatory activity is dependent on consistently low binding energies,which varies between the ligands for the different pockets.-aminobutansyra receptorer av typ A (GABAARs) är de huvudsakligahämmande neurotransmittor-receptorerna i den mänskligahjärnan och moduleras av ett stort antal exogena molekyler, såsomsedativa läkemedel och anestetika. Under det senaste åretsläpptes de första bilderna från cryo-elektronmikroskopi (cryo-EM) av de stängda och desensibiliserade tillstånden i GABAAR,vilket möjliggjorde framgångsrik forskning genom simuleringarav dessa komplexa proteiner. Denna rapport undersöker egenskapernahos de två strukturerna. Specifikt jämförs hydrering avporen, porens radie och hydrofobicitet, medan huvudfokus liggerpå bindningsfickorna för generella anestetika (GA) i den transmembranadomänen, liksom på liganderna propofol, etomidat ochpentobarbital. Dessutom jämförs olika modeller för den saknadestrukturen hos den intracellulära domänen (ICD). Strukturernasimulerades i 1 μs med GROMACS. Användning av sekvensanpassningsom utgångspunkt för olika modeller med heptapeptidenSQPARAA som ersättning för ICD resulterade i stabila strukturermed RMSD för kolkedjan nära 2 Å efter 1 μs. Resultatenav karakterisering av poren visar signifikanta skillnader mellande två tillstånden med tydlig sammandragning vid 9’ positionen idet stängda tillståndet, men också misstänkt felaktig expansion avporen nära toppen i det desensibiliserade tillståndet efter ekvilibrering.Två av fickorna i det desensibiliserade tillståndet avvikervidare från förväntan, genom att vara för begränsade. De andrafickorna var tillräckligt stora för att binda ligander i det desensibiliseradetillståndet, men inte i det stängda, som förväntat. Bindningsanalysenav GA antyder att etomidat binder med fenylringenpekandes mot ICD och att pentobarbital binder med huvudgruppenpekandes mot poren. Analysen tyder också på att GAs kanbinda till varje GA-ficka, medan den modulerande aktiviteten ärberoende av konsekvent låga bindningsenergier, som varierar mellanliganderna för de olika fickorna.
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Hafner, Anne-Sophie. « Regulation of ampa receptor surface trafficking Through auxiliary protein interaction with psd-95 ». Thesis, Bordeaux 2, 2013. http://www.theses.fr/2013BOR22120/document.
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Les récepteurs du glutamate de type AMPA (rAMPA) sont les récepteurs ionotroniques responsables de la majeure partie des courants excitateurs rapides lors de la transmission synaptique dans le système nerveux central. Le nombre de rAMPA stabilisés à la synapse est responsable en partie de l’intensité de la transmission synaptique et de nombreux phénomènes de plasticité synaptique. Les rAMPA se répartissent en trois populations en équilibre dynamique: les récepteurs intracellulaires, les récepteurs extra-synaptiques, et les récepteurs synaptiques stabilisés au niveau de la densité post-synaptique. L’implication des protéines transmembranaires régulatrices des rAMPA (TARP) dans la stabilisation des rAMPA est établie, et repose au moins en partie sur la liaison de la protéine TARP γ-2 avec la protéine d’échafaudage PSD-95. Dans l’hippocampe, siège de nombreux phénomènes de plasticité, l’isoforme γ-8 est particulièrement enrichie. La TARP γ-8 a pour particularité de posséder un domaine C-terminal plus long que son homologue γ-2 et de s’exprimer au niveau synaptique et extra-synaptique. Mon travail de thèse à consisté à étudier les mécanismes moléculaires mis en jeu dans la régulation de la liaison des protéines TARP γ-2 et γ-8 avec la protéine PSD-95, ainsi que l’implication respective des deux isoformes dans la régulation de la mobilité latérale des rAMPA. Les résultats majeurs de cette étude sont : a) l’interaction entre γ-2 et PSD-95 est régulée par la longueur apparent du domaine C-terminal de γ-2 modulée par la phosphorylation; b) γ-8 lie PSD-95 dans les compartiments synaptiques et extra-synaptiques, toutefois cette interaction n’est pas corrélée avec une immobilisation des rAMPA. Ces résultats suggèrent que γ-2 et γ-8 jouent des rôles bien distincts dans l’adressage des rAMPA à la synapseAMPA type glutamate receptors (AMPARs) are ionotropic receptors responsible for most excitatory transmission in the central nervous system. The number of stabilized AMPARs in front of glutamate release sites determines in large part the strength of synaptic transmission and variation in this number is thought to underlie numerous forms of synaptic plasticity. AMPARs are present in three main subcellular pools between which they are in a dynamic equilibrium by processes of trafficking: intracellular receptors, extrasynaptic receptors, and synaptic receptors stabilized at the postsynaptic density (PSD). Transmembrane AMPAR regulatory proteins (TARPs) are known to be implicated in AMPAR stabilization at the synapse through the interaction of TARP γ-2/8 with the scaffolding protein PSD-95. In the hippocampus, a structure exhibiting various synaptic plasticity patterns, γ-8 is the most abundant TARP. This isoform is characterized by a longer C-terminal fragment than γ-2 and a synaptic and extrasynaptic localization. During my Ph.D, I studied the molecular mechanisms involved in the regulation of TARP γ-2 and γ-8 binding to PSD-95 and their respective roles in regulating AMPAR lateral mobility. The main results are: a) γ-2 interaction with PSD-95 is regulated by the apparent length of its C-terminus domain that is modulated by phosphorylation; b) γ-8 binds PSD-95 in synaptic and extrasynaptic compartment however this interaction is not correlated with AMPAR immobilization. Altogether, those results suggest that those two TARP isoforms have independent functional roles
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Cook, Julia Vanessa Foskett. « Site-directed mutagenesis studies of the GnRH and TRH receptors of the pituitary gland ». Thesis, University of Edinburgh, 1996. http://hdl.handle.net/1842/27825.
Texte intégralRésumé :
The aim of this thesis was to study the structure-function relationships of the G-protein coupled GnRH receptor and has focused on the identification of key amino acids involved in GnRH receptor-ligand interactions as well as the role of putative disulphide bridge formation within the receptor itself. In addition, the role of disulphide bridges has also been explored in another G-protein coupled receptor (GPCR), the thyrotrophin-releasing hormone (TRH) receptor. Based on primary amino acid sequence data and computer-assisted molecular models, potentially important amino acids were targeted for study. Site-directed mutagenesis was used to substitute targeted amino acids and following expression of mutant receptors in mammalian cells, receptor binding and second messenger function was measured. In GPCRs two conserved extracellular cysteine (Cys) residues have been postulated to form a covalently linked disulphide bridge structure. In the TRH receptor these residues are positioned at Cys98 and Cys179, in the first and second extracellular loops respectively, whilst in the GnRH receptor they are located at analogous positions Cys114 and Cys195. In conclusion putative disulphide bond formation between extracellular cysteine residues in both the GnRH and TRH receptors is important in maintaining tertiary protein structure. In addition amino acids located in TM II and TM VII are essential for the interactions between GnRH and its receptor. Analysis of structure-function relationships, particularly using this dual biochemical and molecular modelling approach, will greatly facilitate rational drug design. In the light of the enormous clinical applications of GnRH and its analogues, information regarding the mechanisms of hormone-receptor interaction will be of benefit in the development of new and novel drug for clinical use in reproductive medicine.
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Pettersson, Sara. « Development of siRNA against the CYP1A1 gene for trap of endogenous Ah-receptor ligand ». Thesis, Södertörn University College, School of Life Sciences, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:sh:diva-878.
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The aryl hydrocarbon receptor (Ah-receptor) is a member of the bHLH-PAS protein family. The Ah-receptor is a ligand dependent transcription factor, which activates a wide range of genes, most notably the xenobiotica metabolising genes, CYP1A1 and CYP1A2. The biological function of the Ah-receptor is still unknown and an endogenous ligand has yet not been identified. A possible Ah-receptor ligand is 6-formylindolo[3,2-b]carbazole (FICZ). FICZ has a high affinity for the Ah-receptor and is rapidly metabolised by CYP1A1, CYP1A2 and aldehydeoxidase (AOX). To try to trap FICZ or other possible endogenous Ah-receptor ligands, the metabolising enzymes CYP1A1, CYP1A2 and AOX were blocked. This was achieved through chemical blockage of CYP1A1 and CYP1A2 by ellepticin and through silencing with siRNA directed against CYP1A1 and CYP1A2. Successful blockage would be seen as an increase in Ah-receptor dependent XRE-luciferase activity. Chemical blockage of AOX with tungstate did not affect FICZ-dependent XRE-luciferase activation which could indicate that HepG2 cells lack AOX. The chemical blockage of CYP1A1 and CYP1A2 with ellepticin modified the XRE-luciferase response, but did not completely block Ah-receptor activation. In addition it is possible that ellepticin is a ligand for the Ah-receptor. The blockage of CYP1A1 by siRNA was successful; a silencing of CYP1A1 mRNA by at least 50 percent was detected. However due to lack of time it was not tested if the blockage of CYP1A1 and CYP1A2 was sufficient to trap Ah-receptor ligands.
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Almeida, Mônica Moura de. « Participação de Canais Potencial Receptor Transiente (TRP) no mecanismo de ação vasorrelaxante de rotundifolona em artéria mesentérica de rato ». Universidade Federal da Paraíba, 2011. http://tede.biblioteca.ufpb.br:8080/handle/tede/6721.
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Introduction: The Transient Receptor Potential (TRP) superfamily of cation channels is remarkable since it displays greater diversity in activation mechanisms, and are targets for plant-derived compounds. Aim: To investigate the role of TRP channels in the vasorelaxant response of rotundifolone in the superior mesenteric artery from Lyon Normotensive (LN) rats. Methods and Results: Endothelium-denuded artery rings were suspended by platinum hooks for isometric tension recordings. In nominally free-Ca2+ medium, the rings were submitted to successive phenylephrine (Phe) contractions to deplete Ca2+- stores and contracted to CaCl2 (10-2 M). The maximum response (MR) of CaCl2-contractions in presence of nifedipine (10-6 M) (MR = 31.66 ± 2.27 %) were significantly attenuated in the presence of nifedipine plus rotundifolone (3 x 10-4 and 3 x 10-3 M) (MR = 9.30 ± 2.38 and 1.12 ± 0.31 %) or nifedipine plus menthol (10-4 and 10-3 M) (MR = 10.96 ± 1.34 and 1.52 ± 0.82 %). Rotundifolone caused relaxation of vessels pre-contracted with Phe (MR = 100.32 ± 3.88 %; pD2 = 3.59 ± 0.04, n = 6). The vasorelaxant effect induced by rotundifolone was significantly atenuated in the presence of Gd3+ (10-4 M) (MR = 83.74 ± 5.71 %; pD2 = 3.15 ± 0.06); Gd3+ (2.25 x 10-5 or 2 x 10- 6 M) (pD2 = 3.18 ± 0.06 and 3.32 ± 0.03 %) or BCTC (MR = 76.30 ± 2.15 %; pD2 = 3.46 ± 0.04), but no in the presence of ruthenium red, La3+ or Mg2+, nor after TRPV1 desensitization with capsaicin. Menthol caused relaxation of vessels pre-contracted with Phe (MR = 105.07 ± 3.07 %; pD2 = 3.72 ± 0.02). The vasorelaxant effect induced by menthol was significantly potentiated in the presence of ruthenium red (10-5 M), a non-selective TRP channels blocker (pD2 = 4.12 ± 0,04, n = 6). Also, the vasorelaxant response of menthol was significantly attenuated in the presence of La3+ (8 x 10-5 M), non-selective TRP channels blocker (MR = 89.05 ± 1.61 %); Mg2+ (2.25 x 10-3 M), TRPM3, 6 and 7 selective blocker (MR = 90.76 ± 2.94 %); Gd3+ (10-4 M), TRPV4, TRPC1, 3 and 6, TRPM3 and 4 channels blocker (MR = 73.82 ± 5.44 %); Gd3+ (2.25 x 10-5 M), TRPC3 and 6, TRPV4 channels blocker (MR = 88.04 ± 2.33 %); Gd3+ (2 x 10- 6 M), TRPC6 selective blocker (MR = 89,30 ± 3,61 %) or BCTC (2 x 10-6 M), TRPM8 and TRPV1 channels blocker (MR = 66.77 ± 6.05 %), and after TRPV1 desensitization with capsaicin (10-5 M) (RM = 88.96 ± 4.50). The basal tension was reduced by change in the thermostat temperature from 37 ºC to 25ºC and 18ºC (MR = 21.15 ± 0.78 and 28.84 ± 1.03 %). This response was significantly potentiated by rotundifolone (3 x 10-3 M) (MR = 28.01 ± 1.81 and 38.45 ± 1.98 %) or menthol (10-3 M) (MR = 29.87 ± 1.25 and 43.03 ± 2.22 %). In the way similar to menthol, the effects induced by rotundifolone were attenuated in free-Ca2+ medium plus EGTA (MR = 20.42 ± 1.97 and 30.90 ± 2.58 %) or in the presence of BCTC (MR = 17.05 ± 1.94 and 26.48 ± 3.39 %), but not when the vessels were pre-treated with ruthenium red or capsaicin. The RNAm and the protein of the TRPM8 channel are expressed in the superior mesenteric artery from LN rats. Conclusions: These data suggest that rotundifolone induces concentration-dependent relaxation in the mesenteric artery due to inhibition of ROC and SOC channels (probably TRPC1 and TRPC6) and activation of TRPM8 channels.
Introdução: A superfamília Potencial Receptor Transiente (TRP) de canais catiônicos se destaca por exibir uma grande diversidade de mecanismos de ativação, e são alvos de compostos derivados de plantas. Objetivo: Investigar o papel de canais TRP na resposta vasorrelaxante de rotundifolona em artéria mesentérica superior de ratos Normotenso de Lyon (LN). Métodos e Resultados: Anéis de artéria sem endotélio foram suspensos em hastes metálicas para registro de tensão isométrica. Em meio nominalmente sem Ca2+, os anéis foram submetidos a contrações sucessivas com FEN para depleção dos estoques de Ca2+ e contraídos com CaCl2 (10-2 M). O efeito máximo (Emáx) das contrações com CaCl2 na presença de nifedipino (10-6 M) (Emáx = 31,66 ± 2,27 %) foi significativamente atenuado na presença de nifedipino mais rotundifolona (3 x 10-4 e 3 x 10-3 M) (Emáx = 9,30 ± 2,38 e 1,12 ± 0,31 %) e nifedipino mais mentol (10-4 e 10-3 M) (Emáx = 10,96 ± 1,34 and 1,52 ± 0,82 %). Rotundifolona causou relaxamento de vasos pré-contraídos com FEN (Emáx = 100,32 ± 3,88 %; pD2 = 3,59 ± 0,04, n = 6). O efeito vasorrelaxante induzido por rotundifolona foi signigficativamente atenuado na presença de Gd3+ (10-4M) (Emáx = 83,74 ± 5,71 %; pD2 = 3,15 ± 0,06); Gd3+ (2,25 x 10-5 ou 2 x 10-6 M) (pD2 = 3,18 ± 0,06 e 3,32 ± 0,03 %) ou BCTC (Emáx = 76,30 ± 2,15 %; pD2 = 3,46 ± 0,04), mas não na presença de vermeho de rutênio, La3+ or Mg2+, nem após dessensibilização do TRPV1 com capsaicina. Mentol também causou o relaxamento de vasos pré-contraídos com FEN (Emáx = 105,07 ± 3,07 %; pD2 = 3,72 ± 0,02). O efeito vasorrelaxante induzido por mentol foi significativamente potencializado na presença de vermelho de rutênio (10-5 M), um bloqueador não seletivo de canais TRP (pD2 = 4,12 ± 0,04, n = 6) e significativamente atenuada na presença de La3+ (8 x 10-5 M), bloqueador não seletivo de canais TRP (Emáx = 89,05 ± 1,61 %); Mg2+ (2,25 x 10-3 M), bloqueador seletivo dos canais TRPM3, 6 e 7 (Emáx = 90,76 ± 2,94 %); Gd3+ (10-4 M), bloqueador de canais TRPV4, TRPC1, 3 and 6, TRPM3 and 4 (Emáx = 73,82 ± 5,44 %); Gd3+ (2,25 x 10-5 M), bloqueador de canais TRPC3 and 6, TRPV4 (Emáx = 88,04 ± 2,33 %); Gd3+ (2 x 10-6 M), bloqueador seletivo do TRPC6 (Emáx = 89,30 ± 3,61 %) ou BCTC (2 x 10-6 M), bloqueador dos TRPM8 e TRPV1 (Emáx = 66,77 ± 6,05 %), e após a dessensibilização do TRPV1 com capsaicina (10-5 M) (Emáx = 88,96 ± 4,50). A tensão basal foi reduzida por mudança na temperature do banho de 37 ºC para 25ºC e 18ºC (Emáx = 21,15 ± 0,78 e 28,84 ± 1,03 %). Essa resposta foi significativamente potencializada por rotundifolona (3 x 10-3 M) (Emáx = 28,01 ± 1,81 e 38,45 ± 1,98 %) ou mentol (10-3 M) (Emáx = 29,87 ± 1,25 e 43,03 ± 2,22 %). Semelhante ao mentol, os efeitos induzidos por rotundifolona foram atenuados em meio sem Ca2+ mais EGTA (Emáx = 20,42 ± 1,97 e 30,90 ± 2,58 %) ou na presença de BCTC (Emáx = 17,05 ± 1,94 e 26,48 ± 3,39 %), mas não quando os vasos foram pré-tratados com vermelho de rutênio ou capsaicina. O RNAm e a proteína do canal TRPM8 são expressos em artéria mesentérica de ratos LN. Conclusões: Esses dados sugerem que rotundifolona induz relaxamento dependente de concentração em artéria mesentérica devido à inibição de canais ROC e SOC (provavelmente TRPC1 e TRPC6) e ativação de canais TRPM8.
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Benito, Gutiérrez Èlia. « Factores y receptores neurotróficos en el pre-vertebrado arquetípico anfioxo ». Doctoral thesis, Universitat de Barcelona, 2006. http://hdl.handle.net/10803/1873.
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Los factores y receptores neurotróficos son esenciales para el desarrollo y mantenimiento del sistema nervioso vertebrado y contribuyen de manera decisiva en funciones neuronales complejas tales como el aprendizaje, la memoria y el comportamiento social complejo. Dichos genes han sido estudiados en el anfioxo, un invertebrado marino que, por su plano corporal, desarrollo embrionario y genoma prototípico respecto a los vertebrados, es actualmente considerado el pariente vivo más cercano al que fue el ancestro de los vertebrados. Este estudio describe la caracterización a nivel molecular y funcional del primer receptor Trk jamás aislado en un invertebrado, rebatiendo la idea de que los receptores Trk son una innovación de los vertebrados, y sugieriendo que se originó por barajado de exones contenedores de dominios proteicos. Asímismo la expresión de este gen durante el desarrollo embrionario del anfioxo ha revelado ciertas características novedosas respecto al desarrollo de su sistema nervioso. Durante la neurulación se ha provado la migración individual de células ectodérmicas, lo que podría reflejar un comportamiento parecido al de las células de la cresta neural de vertebrados, un tipo de células pluripotentes que dan lugar a un gran número de estructuras únicamente presentes en los vertebrados y totalmente ausentes en el anfioxo. Este trabajo también incluye la caracterización del primer miembro conocido de la familia de las caspasas en el anfioxo, involucradas en muerte neuronal y, además las primeras técnicas desarrolladas para la obtención rutinaria de embriones, con la potencialidad que ello comporta para su manipulación "in vivo", con el objetivo de realizar ensayos funcionales y abrir las puertas a los estudios de Evo-Devo experimental.Neurotrophic factors and their receptors play an essential role in the development and maintenance of the vertebrate nervous system, where they crucially contribute to higher neuronal functions such as learning, memory and complex social behaviour. These genes have been studied for the first time in the cephalochordate amphioxus, which is presently the best stand in for the study of one of the major events in evolution: the invertebrate-vertebrate transition. This work describes the molecular and functional characterisation of the first Trk receptor ever isolated from an invertebrate, refuting the idea that Trk receptors are a vertebrate evolutionary novelty. The results obtained suggest that exon shuffling was a key mechanism to generate a unique ProtoTrk gene, similar to that of amphioxus, which subsequently expanded by gene duplication during vertebrate evolution giving rise to all members of the Trk gene family presently known in higher vertebrates. Furthermore, the expression pattern of this Trk receptor throughout embryonic development revealed certain particularities of the amphioxus nervous system never described before. The embryonic epidermis of amphioxus neurulae contains a cell population able to migrate individually, mimicking the migratory behaviour of the vertebrate neural crest cells, a pluripotent cell type only present in vertebrates and totally absent in amphioxus. This work also includes the characterisation of the first caspase ever isolated in amphioxus and the first approaches towards experimental Evo-Devo through the development of new techniques to obtain amphioxus embryos "a la carte" and to manipulate them "in vivo".
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Weintz, Gabriele Maria. « Phosphoproteome analysis of the macrophage response to toll-like receptor (TRL)-activation ». kostenfrei, 2010. https://mediatum2.ub.tum.de/node?id=807143.
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Ferreira, Paula Dariana Fernandes. « Ausência do receptor Toll-Like 2 ocasionou a formação de lesões periapicais mais extensas e com maior número de osteoclastos em camundongos ». Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/58/58135/tde-30112011-153811/.
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O objetivo deste trabalho foi caracterizar a formação e progressão de lesões periapicais induzidas experimentalmente em dentes de camundongos knockout para receptores toll-like 2 (TLR2 KO) comparados a animais wild-type (WT). As lesões periapicais foram induzidas nos primeiros molares inferiores de 28 camundongos WT e de 27 camundongos TLR2 KO. Decorridos 7, 21 e 42 dias da indução da lesão periapical, os animais foram submetidos à eutanásia em câmara de CO2, as mandíbulas foram removidas e submetidas ao processamento histotécnico. A seguir, cortes representativos foram corados com hematoxilina e eosina (HE), para descrição do tecido pulpar e das regiões apical e periapical, em microscopia óptica convencional, e mensuração da área das lesões periapicais, em microscopia de fluorescência. Espécimes sequenciais foram avaliados por meio de: histoenzimologia para a atividade da TRAP, para identificação de osteoclastos; coloração de Brown & Brenn, para localização de bactérias; e imunoistoquímica, para identificação de marcadores da osteoclastogênese (RANK, RANKL, OPG). Os resultados numéricos obtidos da análise morfométrica da extensão da área das lesões periapicais e do número de osteoclastos foram submetidos à análise estatística por meio dos testes não-paramétricos de Mann-Whitney e Kruskal-Wallis, utilizando o software SAS (Statistical Analysis System) for Windows versão 9.1.3. O nível de significância adotado foi de 5%. Os resultados da coloração de Brown & Brenn e Imunoistoquímica foram expressos de maneira qualitativa. O grupo de animais WT apresentou diferença significante na extensão da área das lesões periapicais e no número de osteoclastos entre os períodos experimentais de 7 e 42 dias (p<0,05) e entre 21 e 42 dias (p<0.05). Por outro lado, no grupo de animais TLR2 KO, as diferenças para a extensão da área das lesões periapicais e número de osteoclastos foram encontradas entre os períodos experimentais de 7 e 21 dias (p<0,05) e entre 7 e 42 dias (p<0,05). Quando os períodos dos grupos foram comparados entre si, foram encontradas diferenças estatísticas entre todos os períodos experimentais, tanto para a análise morfométrica da extensão da área das lesões periapicais, quanto para o número de ostoclastos (p<0,05). A análise descritiva do tecido pulpar e das regiões apical e periapical, por meio da coloração de HE, bem como da localização das bactérias, por meio da coloração de Brown & Brenn, não mostrou diferenças entre os dois grupos de animais. Com relação à Imunoistoquímica, as marcações foram semelhantes entre os dois grupos de animais, exceto para as marcações de RANK, as quais não foram encontradas nas lesões periapicais do grupo de animais TLR2 KO. A partir das metodologias empregadas e dos resultados obtidos pode-se concluir que na ausência do TLR2, os animais desenvolveram lesões periapicais significantemente maiores (com maior presença de osteoclastos) quando comparados aos animais WT, sugerindo o importante papel desse receptor na resposta imune e inflamatória do organismo no sentido de combater a infecção do sistema de canais radiculares e dos tecidos perirradiculares.The aim of the present study was to characterize the formation and progression of periapical lesions experimentally induced in the teeth of toll-like receptors 2 knockout (TLR2 KO) mice compared to wild-type (WT) mice. Periapical lesions were induced in the lower first molars of 28 WT and 27 TLR2 KO mice. After 7, 21 and 42 of periapical lesion induction, the animals were euthanized in a CO2 chamber, and the mandibles were removed and subjected to histotechnical processing. Representative histological sections were stained with hematoxylin and eosin (HE) for description of the features of the pulp tissue and the apical and periapical regions under conventional optical microscopy, and for determination of the size of the periapical lesions under fluorescence microscopy. Sequential specimens were evaluated by: TRAP histo-enzymology for identification de osteoclasts; Brown & Brenn staining for localization of bacteria; and immunohistochemistry for identification of osteoclastogenesis markers (RANK, RANKL, OPG). Data from the morphometric evaluation of the size of periapical lesions and the number of osteoclasts were subjected to statistical analysis by the nonparametric Mann-Whitney and Kruskal-Wallis tests, using the SAS (Statistical Analysis System) software for Windows version 9.1.3. A significance level of 5% was set for all analyses. Data from the Brown & Brenn staining and immunohistochemical analysis were displayed qualitatively. The group of WT mice presented statistically significant difference in the periapical lesion size and number of osteoclasts between the 7- and 42-day experimental periods (p<0.05) as well as between 21 and 42 days (p<0.05). On the other hand, in the group of TLR2 KO mice, significant differences in the periapical lesion size and number of osteoclasts were found between the 7- and 21-day experimental periods (p<0.05) as well as between 7 and 42 days (p<0.05). Comparison of the periods within each group revealed statistically significant differences among all experimental periods for the morphometric evaluation of the size of the periapical lesions and number of osteoclasts (p<0.05). Descriptive analysis of pulp tissue and apical and periapical regions by HE staining and localization of bacteria by Brown & Brenn staining did not show significant differences between the two groups of animals. The immunohistochemical results showed similar immunostaining in both groups of animals, except for RANK expression, which was not observed in the periapical lesions of the TLR2 KO mice. Based on the employed methodology and the obtained results it may be concluded that in the silence of TLR2, the animals developed superior size of periapical lesions (with higher presence of osteoclasts) compared to WT animals, suggesting the important role of this receptor during the immune and inflammatory response against the infection of root canal system and periapical tissues.
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Massullo, Pam. « Aberrant subcellular targeting of the G185R neutrophil elastase mutant associated with severe congenital neutropenia induces premature apoptosis of differentiating promyelocytes & ; expression and function of the transient receptor potential 2 (TRPM2) ion channel in dendritic cells ». Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1172865905.
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Gatto, Mariana. « Análise do perfil transcricional de células THP-1 infectadas com Leishmania infantum/chagasi ênfase no inflamassoma e receptores NODs / ». Universidade Estadual Paulista (UNESP), 2018. http://hdl.handle.net/11449/154046.
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A leishmaniose visceral (LV) é uma doença negligenciada causada por Leishmania donovani na Índia e África ou Leishmania infantum na Europa e América Latina. O desenvolvimento de resposta imune eficaz e subsequente eliminação destes patógenos, requer o reconhecimento inicial da Leishmania, o qual é intermediado por receptores de reconhecimento padrão expressos por células da imunidade inata, entre eles os receptores de ligação a nucleotídeo (NLRs). Alguns NLRs ativam uma plataforma de proteínas, os inflamassomas, responsáveis pela ativação da caspase-1 e maturação de IL-1β e IL-18 e outra classe de NLRs, chamada NODs, ativam vias que culminam na ativação de NF-κB e produção de mediadores inflamatórios. O envolvimento desses receptores na LV ainda é pouco elucidado. Mesmo diante dos mecanismos de defesa do hospedeiro, esses parasitas conseguem sobreviver dentro dos macrófagos utilizando várias estratégias para escapar da resposta imune. Para um melhor entendimento dos mecanismos imunes envolvidos na LV, caracterizamos o perfil transcricional e a formação de inflamassomas e NODsomas de células THP-1 infectadas com L. infantum. Os resultados mostram que a L. infantum não induziu produção de TNF-α, IL-6 e IL-1β e nem ativação de caspase-1 após 8, 24 e 48 horas de infecção. Além disso, a infecção resultou em padrão de expressão gênica similar às células sem estímulo e distinto de células estimuladas com LPS, indicando que os parasitas entram nas células de forma mais silenciosa. Após a infecção houve aumento da expressão de alguns genes como ACTG1, ACTB, CD36 e DUSPs relacionados com vias de motilidade celular e regulação de MAPKs. Os genes CSF1 e CDC20 foram dois dos 30 mais expressos após infecção e estão relacionados com ciclo celular e diferenciação de macrófagos para um perfil anti-inflamatório. O gene GBP1, associado com ativação de inflamassomas, foi sub expresso após a infecção. Além disso, infecção com L. infantum resultou na expressão de poucos genes relacionados com a via dos NLRs, destacando-se entre esses o TNFAIP3 e IL1RN, referentes à modulação negativa dessa via. Os resultados obtidos indicam que a L. infantum entra nas células THP-1 de forma mais silenciosa, desativa vias inflamatórias, entre essas a via de receptores NLRs e evita a montagem de uma resposta imunológica efetora. Provavelmente o parasita usa esses recursos como mecanismos adicionais de escape para garantir sua sobrevivência dentro das células.
Visceral leishmaniasis (VL) is a neglected infectious disease caused by Leishmania donovani in India and Africa or Leishmania infantum in Europe and Latin America. The development of an effective immune response and subsequent elimination of these pathogens requires the initial recognition of the Leishmania that is mediated by pattern recognition receptors expressed in innate immunity cells, such as nucleotide-binding receptors (NLRs). Some NLRs activate a multiprotein platform named inflammasomes, responsible for the activation of caspase-1 and consequent maturation of IL-1β and IL-18; and another class of NLRs, the NODs, activate pathways that trigger NF-κB activation and production of inflammatory mediators. The involvement of NLRs in LV is poorly elucidated. Even in the presence of host defense mechanisms, these parasites can survive within the macrophages by employing successful strategies to escape from immune response. For a better understanding of the immune mechanisms involved in LV, we characterized the transcriptomic profiling and assembly of inflammasomes and NODsomas during infection with L. infantum in THP-1 cells. The results show that L. infantum did not induce the production of TNF-α, IL-6 and IL-1β nor activation of caspase-1 after 8, 24 and 48 hours of infection. In addition, the infection resulted in a pattern of gene expression similar to the non-stimulated cells and distinct from LPS-stimulated cells, indicating that the parasites enter inside cells in a more silent way. After infection, there was increased expression of some genes, such as ACTG1, ACTB, CD36 and DUSPs related to cellular motility and regulation of MAPKs pathways. The CSF1 and CDC20 genes were two of the 30 most expressed after infection and were related to cell cycle pathway and macrophage differentiation to an anti-inflammatory profile. The GBP1 gene, associated with inflammasome activation, was downregulated after infection. In addition, infection with L. infantum resulted in the expression of few genes related to the NLRs pathway, such as TNFAIP3 and IL1RN that are related to down modulation of this pathway. The results indicate that L. infantum enters inside the THP-1 cells more quietly, deactivates inflammatory pathways, including the NLR receptor pathway, and avoids the assembly of an effector immune response. Probably the parasite uses these strategies as additional escape mechanism to ensure its survival within host cells.
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Shang, Ye. « Mechanisms Regulating Transient Receptor Potential Cation Channel A1 (TRPA1) and Their Roles in Nociception and Nociceptive Sensitization ». eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1092.
Texte intégralRésumé :
Nociception is the sensory nervous system that detects harmful stimuli including excessive heat, cold, toxic chemicals, and noxious mechanical stimulations. Transient receptor potential (TRP) channels are a group of evolutionarily conserved ion channels consisting of 4 subunits, each with 6 transmembrane spans, and detect a variety of external and internal nociceptive stimuli. Due to their critical roles in nociception, it is essential to understand the mechanisms that regulate TRP channels and subsequent nociception. Here, I investigated two distinct types of regulation of Drosophila transient receptor potential cation channel A1 (TrpA1): regulation via the expression of different TrpA1 isoforms, and via its binding with associated proteins. I found that one of the TrpA1 isoforms, TrpA1(E), inhibits the thermal responses of other TrpA1 isoforms in vitro. I also identified potential TrpA1 binding partners through Co- immunoprecipitation (Co-IP) and mass spectrometry analysis. These binding partners need further validation and characterization through biochemical, cellular, and behavioral assays to illustrate their roles in nociception, and may serve as potential drug targets for chronic pain.
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Unger, Nicholas T. « Blockade of the Transient Receptor Potential Vanilloid (TRPV) by Ruthenium Red Does Not Suppress Hypothalamic Neuronal Thermosensitivity ». The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1331060091.
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Anandarajan, Mugilan. « The expression and function of airway epithelial Transient Receptor Potential (TRP) channels in hypersensitive airways in children with respiratory problems ». Thesis, Queen's University Belfast, 2017. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.725331.
Texte intégralRésumé :
Aim' To determine whether the bronchial epithelial cells from young children with different wheezing or coughing phenotypes have increased expression of transient receptor potential (TRP) cation channel receptors compared to normal. Hypotheses to be tested: TRPV1, TRPV4, TRPA1 and TRPM8 receptors are expressed and over-expressed on the bronchial epithelium of young children with post bronchiolitis wheezing / episodic viral induced wheezing (non- asthmatic wheezers), classical atopy asthma and coughers compared to normal subjects. Methodology: Freshly isolated bronchial epithelial cells from children were tested for expression of TRP channels and their functional role by microfluorimetry, immunocytochemistry, confocal live cell imaging, patch clamping and qt- PCR. Results: The experiments conducted in the present study has aided in inferring that TRPV1, V4, A1 and M8 channels are expressed and are functional in bronchial epithelial cells. The channels are expressed in sub cellular organelles in the peri nuclear and nuclear region and are involved in calcium signaling. Our data from microfluorimetry and confocal live cell experiments strongly suggests that TRPM8, V1, V4 and A1 channels are functionally active as evidenced by their ability to 2+ contribute to PBEC Ca signaling and there were differences in response of freshly isolated bronchial epithelial cells between asthmatic and healthy children. However further tests needed to be carried out with more patient samples to analyze the significance of the differences. The analysis of responses from confocal live cell imaging suggested that the calcium whole cell responses and the peak responses in microfluorimetry experiments were increased in most asthmatic cells in comparison to Freshly isolated bronchial epithelial cells from healthy children. Despite the number of patient samples and cells analyzed this is a significant finding suggesting possible up regulation or over expression of the TRP channels in children with asthma. The present study has shown the presence of TRPV1, V4, A1 and M8 channels in bronchial epithelium with possible increased expression or upregulation of these channels in asthma compared to normal healthy children.
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Guiton, Michelle. « Molecular basis of signal transduction by the Trk family of receptor tyrosine kinases ». Thesis, University of Bristol, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296366.
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Wei, Shuo. « Peroxisome Proliferator-Activated Receptor γ (PPARγ)-Independent Antitumor Effect of Thiazolidinediones ». The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1259167390.
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Liviero, Filippo. « La modulazione dei canali transient receptor potential v1 e a1 con prostaglandina-e2e bradichinina è associata adaumento della risposta tussigena alla capsaicina ed a variazionidella regolazioneautonomica del ritmo cardiaco in soggetti sani ». Doctoral thesis, Università degli studi di Padova, 2019. http://hdl.handle.net/11577/3425778.
Texte intégralRésumé :
BACKGROUND:
Vi sono evidenze in modelli animali che l’inalazione di particolato fine (PM), attivi i recettori polmonari TRPV1 e TRPA1 e attraverso una modulazione del sistema nervoso centrale possa influenzare la regolazione autonomica dell'attività cardiaca. Questa ipotetica via neurogena, potrebbe essere responsabile degli effetti cardiovascolari avversi osservati in soggetti suscettibili dopo esposizioni acute a PM.
OBIETTIVI:
Verificare che l'attività di TRPV1 e TRPA1 può essere modulata in vivo dall’inalazione di prostaglandina-E2 (PGE2) e bradichinina (BK), e che i cambiamenti nell'attività dei canali TRP interferiscano con la regolazione autonomica del ritmo cardiaco nell’uomo. In un gruppo di volontari sani abbiamo valutato:
1. la risposta tussigena alla capsaicina (CPS) ed alla cinnamaldeide (CMA), agonisti esogeni rispettivamente dei canali TRPV1 e TRPA1, somministrati per via inalatoria prima e dopo l'inalazione di PGE2 e BK, agonisti endogeni in grado di attivare in vitro i canali TRP;
2. la variabilità della frequenza cardiaca (HRV) al momento della modulazione dei canali TRP con PGE2 e BK.
È stato inoltre verificato:
3. il meccanismo molecolare della modulazione del canale TRPV1 in vitro su cellule HeLa trasfettate con la forma wild-type del TRPV1;
4. se la presenza di polimorfismi funzionali (SNPs) di TRPV1 spieghi la variabilità della risposta tussigena alla CPS e se modifichi la risposta tussigena alla modulazione dei canali TRP con PGE2 e BK.
MATERIALI E METODI:
1. Sono stati reclutati 20 volontari sani, 17 dei quali hanno effettuato l’inalazione di PGE2 e BK o diluente, in modo randomizzato e in doppio cieco. Subito dopo, ogni soggetto è stato sottoposto al test di stimolazione specifica del recettore TRPV1 con CPS e TRPA1 con CMA.
2. In 12 dei volontari sani arruolati è stata misurata la HRV tramite la registrazione dell’elettrocardiogramma (ECG), avvenuta dopo l’inalazione di diluente, PGE2 e BK. Abbiamo analizzato tre variabili delle componenti spettrali nel dominio della frequenza che rappresentano indici di modulazione simpatica, vagale e del bilancio simpatico-vagale.
3. Abbiamo monitorato la funzionalità del canale TRPV1 misurando la concentrazione di [Ca2+] nelle cellule HeLa dopo trattamento con CPS e CMA. Abbiamo trasfettato le cellule HeLa con il canale umano TRPV1 per misurarne la funzionalità, dopo il pre-trattamento con dosi crescenti di PGE2, BK o particolato di scarico diesel (DEP) e successiva stimolazione con CPS.
4. Tutti i volontari sono stati caratterizzati per la risposta tussigena alla CPS. Abbiamo analizzato il DNA di ciascuno per caratterizzare sei SNPs di TRPV1.
RISULTATI:
1. L'inalazione di PGE2 e BK ha determinato un aumento significativo della risposta tussigena indotta dalla CPS, indicando un aumento di sensibilità del TRPV1. La modulazione del TRPA1 ha mostrato cambiamenti inconsistenti della risposta tussigena indotta dalla CMA.
2. L'inalazione di PGE2 e BK ha modificato significativamente l’HRV comportando uno sbilanciamento della regolazione autonomica del ritmo cardiaco a favore del sistema simpatico rispetto al vagale.
3. Il pretrattamento con PGE2 o BK delle cellule HeLa che esprimono il TRPV1, non ha modificato le risposte cellulari indotte da CPS, dimostrando come nel nostro modello sperimentale, questi due mediatori non sensibilizzino direttamente il canale TRPV1. Il trattamento con il DEP ha aumentato significativamente le risposte cellulari mediate da CPS, indicando che TRPV1 è direttamente sensibilizzato dal particolato.
4. La variabilità della risposta tussigena alla CPS tra soggetti sani è spiegata da molteplici SNPs del canale TRPV1. Il contributo maggiore alla sensibilità in termini di risposta tussigena alla CPS in vivo è dovuto alla presenza di quattro SNPs combinati: I315M; I585V; T469I; P91S.
Questi dati supportano l’ipotesi che l’inalazione di PM, interferendo con la funzione dei TRP, induca effetti cardiovascolari acuti in soggetti suscettibili.BACKGROUND There is evidence in animal models, that particulate (PM) inhalation, activates TRPV-1 and TRPA-1 pulmonary receptors and may change the autonomic regulation of cardiac activity, through a modulation of afferent signals in the central nervous system. This hypothetical neurogenic pathway could explain the adverse cardiovascular effects observed in susceptible subjects after acute PM exposures. OBJECTIVES The aim of the study was to verify that the activity of TRPV-1 and TRPA-1 can be modulated in vivo by inhaled stimuli and that changes in TRP channels activity modify the autonomic regulation of heart rhythm. To do this we evaluated in a group of healthy volunteers: 1. Cough response to capsaicin (CPS) and cinnmaldeide (CMA), exogenous agonists of TRPV-1 and TRPA-1 channels, before and after inhalation of PGE2 and BK, endogenous mediators that activate TRP channels in vitro; 2. Heart rate variability (HRV) after modulation of TRP channels with PGE2 and BK. We also evaluated: 3. The molecular mechanism of TRPV-1 channel modulation in vitro, on HeLa cells transfected with the TRPV-1 wild-type; 4. Whether presence of functional polymorphisms (SNPs) of TRPV-1 explains the variability of cough response to CPS and whether it modifies cough response to the modulation of TRP channels with PGE2 and BK. METHODS 1. 20 healthy volunteers were recruited. 17 performed PGE2 and BK or diluent inhalation, in a randomized double-blind fashion. Immediately after inhalation of the modulators, the sensitivity of TRPV-1 to CPS and of TRPA-1 to CMA was assessed with cough challenge. 2. Heart rate variability (HRV) was tested in 12 of the enrolled healthy volunteers recording the electrocardiogram (ECG) after inhalation of diluent, PGE2 and BK. We analyzed the variables of spectral components in the frequency domain, that represent indexes of sympathetic, vagal and sympathetic-vagal balance. 3. Functional properties of TRPV-1 channel were evaluated measuring [Ca2 +] in HeLa cells after treatment with CPS and CMA. HeLa cells were transfected with the TRPV-1 human channel. [Ca2 +] in HeLa cells was measured after pre-treatment with increasing doses of PGE2, BK or diesel exhaust particulate matter (DEP) followed by CPS stimulation. 4. All volunteers were characterized according to cough response to the CPS. We analyzed the DNA of each subjects to assess the presence of six functional polymorphisms (SNPs) of TRPV-1. RESULTS 1. Inhalation of PGE2 and BK is associated with a significant increase of cough response induced by CPS, while inconsistent changes after stimulation of TRPA-1 with CMA were detected. 2. Inhalation of PGE2 and BK significantly modifies HRV, leading to an imbalance of the autonomic regulation of heart rhythm. In particular we detected an upregulation of the sympathetic system and a downregulation of the vagal system. 3. Pretreatment with PGE2 or BK of HeLa cells expressing TRPV-1 did not modify CPS-induced cellular responses, demonstrating that in our experimental model, these two mediators do not directly sensitize the TRPV-1 channel. Treatment with DEP significantly increased TRPV-1-mediated cellular responses, indicating that it is directly sensitized by particulate matter. 4. We demonstrated that the variability of cough response to CPS between healthy subjects is partially explained by multiple SNPs of the TRPV-1 channel. The major contribution to sensitivity in terms of cough response to CPS in vivo is due to the combination of four SNPs: I315M; I585V; T469I; P91S. However, the modulation of TRPV-1 was irrespective of the presence of SNPs. These data support the hypothesis that PM inhalation, interfering with the function of TRPs, induces acute cardiovascular effects in susceptible subjects.
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Petersson, Marcus. « Beyond AMPA and NMDA : Slow synaptic mGlu/TRPC currents : Implications for dendritic integration ». Licentiate thesis, KTH, Computational Biology, CB, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-24833.
Texte intégralRésumé :
In order to understand how the brain functions, under normal as well as pathological conditions, it is important to study the mechanisms underlying information integration. Depending on the nature of an input arriving at a synapse, different strategies may be used by the neuron to integrate and respond to the input. Naturally, if a short train of high-frequency synaptic input arrives, it may be beneficial for the neuron to be equipped with a fast mechanism that is highly sensitive to inputs on a short time scale. If, on the contrary, inputs arriving with low frequency are to be processed, it may be necessary for the neuron to possess slow mechanisms of integration. For example, in certain working memory tasks (e. g. delay-match-to-sample), sensory inputs may arrive separated by silent intervals in the range of seconds, and the subject should respond if the current input is identical to the preceeding input. It has been suggested that single neurons, due to intrinsic mechanisms outlasting the duration of input, may be able to perform such calculations. In this work, I have studied a mechanism thought to be particularly important in supporting the integration of low-frequency synaptic inputs. It is mediated by a cascade of events that starts with activation of group I metabotropic glutamate receptors (mGlu1/5), and ends with a membrane depolarization caused by a current that is mediated by canonical transient receptor potential (TRPC) ion channels. This current, denoted ITRPC, is the focus of this thesis.
A specific objective of this thesis is to study the role of ITRPC in the integration of synaptic inputs arriving at a low frequency, < 10 Hz. Our hypothesis is that, in contrast to the well-studied, rapidly decaying AMPA and NMDA currents, ITRPC is well-suited for supporting temporal summation of such synaptic input. The reason for choosing this range of frequencies is that neurons often communicate with signals (spikes) around 8 Hz, as shown by single-unit recordings in behaving animals. This is true for several regions of the brain, including the entorhinal cortex (EC) which is known to play a key role in producing working memory function and enabling long-term memory formation in the hippocampus.
Although there is strong evidence suggesting that ITRPC is important for neuronal communication, I have not encountered a systematic study of how this current contributes to synaptic integration. Since it is difficult to directly measure the electrical activity in dendritic branches using experimental techniques, I use computational modeling for this purpose. I implemented the components necessary for studying ITRPC, including a detailed model of extrasynaptic glutamate concentration, mGlu1/5 dynamics and the TRPC channel itself. I tuned the model to replicate electrophysiological in vitro data from pyramidal neurons of the rodent EC, provided by our experimental collaborator. Since we were interested in the role of ITRPC in temporal summation, a specific aim was to study how its decay time constant (τdecay) is affected by synaptic stimulus parameters.
The hypothesis described above is supported by our simulation results, as we show that synaptic inputs arriving at frequencies as low as 3 - 4 Hz can be effectively summed. We also show that τdecay increases with increasing stimulus duration and frequency, and that it is linearly dependent on the maximal glutamate concentration. Under some circumstances it was problematic to directly measure τdecay, and we then used a pair-pulse paradigm to get an indirect estimate of τdecay.
I am not aware of any computational model work taking into account the synaptically evoked ITRPC current, prior to the current study, and believe that it is the first of its kind. We suggest that ITRPC is important for slow synaptic integration, not only in the EC, but in several cortical and subcortical regions that contain mGlu1/5 and TRPC subunits, such as the prefrontal cortex. I will argue that this is further supported by studies using pharmacological blockers as well as studies on genetically modified animals.
QC 20101005
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Moughal, Noreen Akhtar. « S1P,LPA and TRK a receptor expression, activation and signal transduction in various cell types ». Thesis, University of Strathclyde, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.487875.
Texte intégralRésumé :
Lysophosphatidate (LPA) binds to a family of G-protein coupled receptors (GPCR). Three receptors belong to the endothelial differentiation gene (EDG) family, namely LPA1-3. whereas another two receptors LPA4-5 are evolutionary distant. The LPA1receptor couples to effectors via the heterotrimeric G-protein Gi to stimulate activation of the p42/p44 MAPK pathway.