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1
Lucius, Alexander [Verfasser]. "Characterization of temperature-sensitive transient receptor potential channel melastatin 8 (TRPM8) in cultivated human ocular surface cells / Alexander Lucius." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2017. http://d-nb.info/1126503886/34.
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Wang, Qian, and 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.
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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
3
Chen, Wenchun [Verfasser], and Bernhard [Gutachter] Nieswandt. "Studies on the role of calcium channels and the kinase domain of transient receptor potential melastatin-like 7 (TRPM7) in platelet function / Wenchun Chen. Gutachter: Bernhard Nieswandt." Würzburg : Universität Würzburg, 2014. http://d-nb.info/1111783284/34.
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Pimentel, Montero Fátima Elizabeth. "Modulation of transient receptor potential melastatin 8 by protein kinase C /." Available to subscribers only, 2005. http://proquest.umi.com/pqdweb?did=1075689361&sid=10&Fmt=2&clientId=1509&RQT=309&VName=PQD.
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Stokes, Alexander James. "Regulatory interactions of transient receptor potential channels." Thesis, University of Warwick, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.418114.
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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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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.
8
Ogawa, Nozomi. "Detection of cellular redox status by transient receptor potential channels." 京都大学 (Kyoto University), 2016. http://hdl.handle.net/2433/215577.
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Pabbidi, Reddy M. "Role of transient receptor potential channels in diabetic peripheral neuropathy /." Available to subscribers only, 2007. http://proquest.umi.com/pqdweb?did=1456284721&sid=5&Fmt=2&clientId=1509&RQT=309&VName=PQD.
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Bomben, Valerie Christine. "Role of transient receptor potential canonical channels in glioma cell biology." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2010. https://www.mhsl.uab.edu/dt/2010p/bomben.pdf.
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Ghavideldarestani, Maryam. "Role of transient receptor potential channels in mammalian oviduct and uterine epithelia." Thesis, University of Hull, 2011. http://hydra.hull.ac.uk/resources/hull:6068.
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Calcium is an important secondary messenger and plays a major role in cell function, including proliferation, cell growth, secretion and death .It also plays a critical role in uterine smooth muscle contraction and embryo implantation. This thesis is concerned with calcium homeostasis in epithelial tissue lining the oviduct and uterus which are key players in early reproductive events, being involved in gamete transport, sperm capacitation and providing the micro-environment for the gametes and early embryo. Calcium transport across epithelial cells is either via tight junctions or calcium channels, specifically, members of the transient receptor potential (TRP) channel superfamily and the Na+/Ca2+ exchanger. TRP channels are an important class of calcium channels with more than 28 identified members and their potential involvement in calcium transport in uterus and oviduct epithelia has yet to be determined. The aim of this study was to discover which TRPC isoforms are expressed in epithelial cells lining the female reproductive tract in the bovine and human. Gene expression of TRPC channels changes was measured throughout the oestrous cycle in bovine oviduct and uterine epithelial cells using Real-Time PCR, while immunohistochemistry, immunocytochemistry and western blotting were used to discover the localization of TRPC channels in oviduct/uterine epithelium and changes in protein expression of TRPC isoforms induced by sex hormones. . to The physiological role of TRPC isoforms in regulating intracellular calcium concentration in bovine oviduct epithelial cells was determined using a calcium assay approach and finally. the potential clinical relevance of a possible role of TRP channels in female reproduction was investigated.# OF 7 members of TRPC family, TRPC1, 2, 3, 4 and 6 were expressed in bovine oviduct and uterine epithelia. In human endometrium, TRPC1, 6 and 7 genes were detected. Expression levels of all TRPC isoforms present in both bovine oviduct and uterine epithelia changed throughout the oestrous cycle. 17β-estradiol, FSH and LH individually and in combination up-regulated gene expression of TRPC isoforms in bovine oviduct epithelial cells. However, progesterone inhibited the upregulatory effect of 17β-estradiol, FSH and LH on TRPCs gene expression. TRPC1 and TRPC6 which are the common TRPC isoforms in bovine oviduct/uterine epithelium and human endometrium were localized on the apical, basal and lateral membranes of the epithelial tissue in bovine oviduct/uterus and human endometrium. TRPC isoforms were physiologically active in bovine oviduct epithelial cells (BOEC). SKF96365 which is a general TRP channel blocker inhibited the calcium influx into BOEC. Furthermore, Hyperforin which is a TRPC6 channel activator increased the intracellular calcium concentration in BOEC. TRPC1, 6 and 7 expression in endometrium of patients being treated for infertility by IVF illustrated that gene expression of TRTPC1 and 6 were up regulated in the endometrium of the IVF patients compared to controls. However, gene expression of TRPC7 in IVF patients was downregulated compared to that of the endometrium of the control group. Gene expression of TRPC6 and 7 in endometrium of women with Poly Cystic Ovarian Syndrome (PCOS) who have higher level of LH and normal FSH level, alongside the absence of the post-ovulatory increase in progesterone secretion, were up -regulated compared to that of the control group. However, the expression level of TRPC1 in endometrium of PCOS patients was not significantly different compared to the control group. Gene expression of TRPC isoforms in the epithelia lining the female reproductive tract is possibly regulated by sex hormones via nuclear factor-kappa B (NF-КB) signalling pathway. However, further investigation is required to determine the mechanisms underlying the endocrine regulation of TRPC channels.
12
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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Mergler, Stefan, Monika Valtink, Sumioka Takayoshi, Yuka Okada, Masayasu Miyajima, Shizuya Saika, and Peter S. Reinach. "Temperature-Sensitive Transient Receptor Potential Channels in Corneal Tissue Layers and Cells." Karger, 2014. https://tud.qucosa.de/id/qucosa%3A71636.
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We here provide a brief summary of the characteristics of transient receptor potential channels (TRPs) identified in corneal tissue layers and cells. In general, TRPs are nonselective cation channels which are Ca ²⁺ permeable. Most TRPs serve as thermosensitive molecular sensors (thermo-TRPs). Based on their functional importance, the possibilities are described for drug-targeting TRP activity in a clinical setting. TRPs are expressed in various tissues of the eye including both human corneal epithelial and endothelial layers as well as stromal fibroblasts and stromal nerve fibers. TRP vanilloid type 1 (TRPV1) heat receptor, also known as capsaicin receptor, along with TRP melastatin type 8 (TRPM8) cold receptor, which is also known as menthol receptor, are prototypes of the thermo-TRP family. The TRPV1 functional channel is the most investigated TRP channel in these tissues, owing to its contribution to maintaining tissue homeostasis as well as eliciting wound healing responses to injury. Other thermo-TRP family members identified in these tissues are TRPV2, 3 and 4. Finally, there is the TRP ankyrin type 1 (TRPA1) cold receptor. All of these thermo-TRPs can be activated within specific temperature ranges and transduce such inputs into chemical and electrical signals. Although several recent studies have begun to unravel complex roles for thermo-TRPs such as TRPV1 in corneal layers and resident cells, additional studies are needed to further elucidate their roles in health and disease.
14
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
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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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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.
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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.
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Che, Hui, and 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.
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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
18
Kato, Kenta. "Characterization of bioactive molecules using genetically engineered ion channels." 京都大学 (Kyoto University), 2010. http://hdl.handle.net/2433/120897.
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Katisart, Teeraporn. "Transient receptor potential function in bladder from control and streptozotocin treated rats." Thesis, University of Hertfordshire, 2011. http://hdl.handle.net/2299/6039.
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Diabetic cystopathy is a chronic and common complication of diabetes with a classical triad of symptoms; decreased bladder sensation, increased bladder capacity and impaired detrusor muscle contractility (Hunter and Moore, 2003). In animal models of diabetes such as streptozotocin-induced diabetes in the rat, abnormalities of bladder function have been reported (Longhurst and Belis, 1986). The prototypic TRPV channel, TRPV1, is activated by capsaicin, which has been shown to cause contraction of the rat bladder (Saitoh et al., 2007), and this is reduced in STZ-diabetic rat bladder (Pinna et al., 1994). Therefore we hypothesize that TRPV1 function will be reduced in the diabetic bladder. The aim of this study are the following: Firstly, to investigate the effect of the streptozotocin (STZ) model of diabetes on a range of TRP channel functions in the urinary bladder smooth muscle preparation using TRP channel agonists and antagonists and to study the neurotransmitters involved in the contractile or relaxant responses. Some studies were also performed on colon tissues. Secondly, to explore the involvement of cholesterol modudation in TRP channel signalling. Thirdly, to study the change in TRP channel response with time following the treatment with streptozotocin. The results showed that the contractile responses to the TRPV1 agonist capsaicin, TRPV4 agonist 4-α-PDD, and TRPA1 agonist allyl isothiocyanate were significantly reduced in diabetic bladder. The selective TRPV1 antagonist, SB-366791, inhibited the contractile responses to capsaicin confirming the involvement of TRPV1 channels. The effect of diabetes is unlikely to be at the level of contractile machinery since the contractile responses to muscarinic receptor agonist carbachol were not significantly reduced in diabetic tissues. It is reported for the first time that the combination of neurokinin 1 and 2 antagonists GR-205171 and SB-207164 inhibited the contractile responses to capsaicin suggesting that a neurokinin may be the neurotransmitter involved in the capsaicin responses. In addition, the reduction of the responses to capsaicin in STZ-induced diabetic tissues occurred not only in urinary bladder but also in colon. Cholesterol-PEG significantly lowered the maximal contractile responses to capsaicin of rat bladder strips. Methyl-β-cyclodextrin, α-cyclodextrin and β-cyclodextrin at the same concentrations enhanced the contractile responses to capsaicin in the control and diabetic rat bladder strips. These effects of cyclodextrin are specific to capsaicin activated contractions and not seen with TRPA1 activation, suggesting that the effects are not mediated downstream of channel activation. Since α-cyclodextrin does not sequester cholesterol, the enhanced responses to cyclodextrins may not be due to the cholesterol modulations. Instead, theses novel findings may possibly occur by changing the local membrane lipid environment of the TRPV1 channel. As early as 36 hours after induction of diabetes by STZ, the contractile responses to capsaicin were significantly reduced in comparison to those of the controls and this reduction persisted until the eight weeks time point. In contrast, responses to the TRPA1 agonist allyl isothiocyanate were not affected at early time points but were reduced one week after STZ treatment. This detailed time course analysis suggests that there are novel mechanisms of modulation of the TRPV1 channels in this STZ model. In conclusion, in the rat urinary bladder or colon preparations, diabetes mellitus using STZ animal model caused 1) the impairment of a number of TRP channel subfamily functions, TRPV1, TRPV4 and TRPA1 but not TRPM8. The combination of NK1 and NK2 antagonists significantly inhibited the responses to capsaicin. This may suggest the involvement of neurokinin in postsynaptic transmission in rat bladder following the activation of TRPV1 channel, 2) the impairment caused by STZ-induced diabetes occurred very early (within 36 hours after diabetes induction) in TRPV1 channel but not TRPA1 channel. There are specific early effects of STZ treatment on TRPV1 channel function at a time when other afferent nerve terminal channels (TRPA1) are functioning normally, suggesting that early onset of dysfunction in TRPV1 signalling may not merely be the consequence of nerve damage, 3) the mechanism of this impairment may not be the effect of neuropathy on neurotransmitter release or nerve damage. Improving the responsiveness of nerves of bladder in diabetic patients might be of therapeutic benefit. The present studies suggest that it is possible to enhance function using indirect modulators such as bradykinin which potentiated the TRPV1 channel function in diabetic rat bladders.
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Ni, Dan. "THERMAL SENSITIVITY OF VAGAL PULMONARY SENSORY NEURONS: ROLE OF TRANSIENT RECEPTOR POTENTIAL VANILLOID CHANNELS." Lexington, Ky. : [University of Kentucky Libraries], 2008. http://hdl.handle.net/10225/944.
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Thesis (Ph. D.)--University of Kentucky, 2008.Title from document title page (viewed on December 10, 2008). Document formatted into pages; contains: x, 73 p. : ill. (some col.) Includes abstract and vita. Includes bibliographical references (p. 62-71).
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McNeill, Matthew Scott. "The Transient Receptor Potential Melastatin 7 is required for early melanophore survival and facets of both embryonic and larval motility in zebrafish." Diss., University of Iowa, 2009. https://ir.uiowa.edu/etd/1162.
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The Transient Receptor Potential, Melastatin-like 7 (TRPM7) protein is composed of a long amino terminus, 6 trans-membrane domains, and a carboxy terminal α-kinase domain; TRPM7 tetramers form non-selective cation channels with unusual permeability to Mg2+. TRPM7 is thought to be expressed in all cell types, and studies conducted primarily on cultured cells have implicated TRPM7 in cellular functions that include cell adhesion, synaptic vesicle release, kidney cation balance, differentiation, survival, and cellular magnesium homeostasis. The full extent of its physiological functions in vivo remains elusive because mouse TRPM7 homozygous null mutants die at embryonic stages. By contrast, zebrafish homozygous for hypomorphic alleles of trpm7 survive for two weeks post fertilization, making it possible to study the physiological consequences of Trpm7 deficiency in a living organism. My work primarily utilizes homozygous animals carrying the trpm7b508 allele, which we suspect encodes a non-functional protein for three reasons. This protein variant is predicted to lack a kinase domain, patch clamp studies fail to detect current, and morpholino knockdown of Trpm7 yields a similar phenotype. Herein, we explore the mechanisms behind each of three phenotypes in trpm7b508 homozygous embryos, i.e., trpm7 mutants. First, we find that cell death of embryonic melanophores in trpm7 mutants is not by apoptosis, and it is dependent upon melanin synthesis and the ion channel Trpm2. Second, we show that paralysis of trpm7 mutants is rescued by surgical opening of the circulatory system to surrounding media, implying that paralysis results from an organismal ion imbalance. Third, we report a variety of findings supporting the model that abnormally low levels of spontaneous swimming in larval trpm7 mutants results from reduced dopamine signaling. We find that specific populations of catecholaminergic neurons are reduced in mutants relative to their unaffected siblings, and that mutants are sensitized to the neurotoxic effects of 1-Methyl-4-phenylpyridinium iodide (MPP+). Together, these results suggest that Trpm7 has a role in ameliorating the toxic effects of reactive oxygen species in certain populations of melanophores and neurons. These findings advance understanding of the function of TRPM7 during embryonic development, and may have relevance to the gene-environment interaction behind certain neurodegenerative conditions.
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Liu, Ying [Verfasser]. "Regulation of transient receptor potential canonical channels TRPC3 and TRPC6 in kidney diseases / Ying Liu." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2013. http://d-nb.info/103109749X/34.
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Shaifta, Yasin Mohammad. "Transient receptor potential channels (TRPC) in human cells : characterisation using over expression and knock-down." Thesis, King's College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.429098.
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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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Cai, Shiwei. "The transient receptor potential channel 1 (TRPC1) mediates calcium-regulated differentiation in oral gingival keratinocytes /." Thesis, Connect to this title online; UW restricted, 2004. http://hdl.handle.net/1773/6390.
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Grimm, Christian [Verfasser]. "Endolysosomal Cation Channels of the Transient Receptor Potential Superfamily : Physiology, Pharmacology, and Mouse Models / Christian Grimm." München : GRIN Verlag GmbH, 2014. http://d-nb.info/1067618155/34.
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Clarke, Rebecca. "An in vitro model for the study of transient receptor potential channels on human sensory neurons." Thesis, Queen's University Belfast, 2015. https://pure.qub.ac.uk/portal/en/theses/an-in-vitro-model-for-the-study-of-transient-receptor-potential-channels-on-human-sensory-neurons(0030aff3-6cb4-43bb-9a40-3e5cbc24c4bc).html.
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Sensory neurons are responsible for detecting noxious chemical, mechanical and thermal stimuli and relaying the information to the central nervous system. They also contribute to local neurogenic inflammation via the release of neuropeptides. Sensory neurons express a variety of ion channels, including the transient receptor potential (TRP) channels. TRP channels are one of the main families of ion channels responsible for nociception and are desirable targets for analgesic and anti-inflammatory therapies. TRP channel studies on human sensory neurons has been hampered by the fact that peripheral neurons lack theis cell bodies, which are housed in neuronal ganglia and are inaccessible via peripheral tissue biopsy. To overcome this limitation we have differentiated human dental pulp stem cells towards a neuronal phenotype, termed peripheral neuronal equivalebts (PNEs), which have their cell bodies present. Microfluorimetric and electrophysiological techniques have demonstrated the functional expression of TRP channels on PNEs, specifically TRPA 1 and TRPV1. Therefore PNEs represent a novel source of functional human sensory neurons suitable for in vitro TRP channel studies. In vivo, neuronal TRP channels become hypersensitised in inflammatory and infectious environments however the exact mechanism through which this occurs is unknown. PNEs pre-treated with pro-inflammatory cytokines generated larger responses to TRP channel agonists when compared to untreated PNEs however no alterations in TRP channel gene expression were observed. PNEs infected with human rhinovirus also show no change in TRP channel gene expression suggesting that TRP channel sensitisation, rather than upregulation, contributes to nerve hypersensitivity.
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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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Solanki, Sumeet A. ""Novel Role of the Transient Receptor Potential Canonical 3 (TRPC3) channel in Macrophage Apoptosis: Implications in Atherosclerosis”." University of Toledo Health Science Campus / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=mco1492707181753622.
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Stenger, Bernhard [Verfasser], and Harald [Akademischer Betreuer] Mückter. "Transient receptor potential A1 channels and their role in the cytotoxicity of sulfur mustard / Bernhard Stenger ; Betreuer: Harald Mückter." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2018. http://d-nb.info/116394887X/34.
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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.
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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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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.
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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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Mertens, Charlotte Nora [Verfasser]. "Functional expression of thermo-sensitive transient receptor potential channels in cultivated human corneal endothelial cells (HCEC-12) / Charlotte Nora Mertens." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2015. http://d-nb.info/1075757304/34.
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Chretien, Chloé. "Un nouvel acteur dans la détection hypothalamique du glucose : les canaux Transient Receptor Potential Canonical (TRPC)." Thesis, Dijon, 2015. http://www.theses.fr/2015DIJOS027/document.
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L’hyperglycémie est détectée et intégrée au niveau de l’hypothalamus médio-basal (MBH) qui inhibe la prise alimentaire et déclenche la sécrétion d’insuline. Le MBH renferme des neurones spécialisés gluco-sensibles (GS) qui détectent directement ou indirectement des variations de la concentration extracellulaire en glucose. Dans une première étude, nous suggérons que la détection indirecte du glucose par les neurones GS hypothalamiques repose sur la libération d’endozépines par les astrocytes, un gliotransmetteur connu pour inhiber la prise alimentaire en réponse à l’hyperglycémie. Nous travaux montrent que les endozépines activent spécifiquement les neurones à pro-opiomélanocortine (POMC) du MBH pour générer leur effet anorexigène. Dans une seconde étude, nous montrons que la détection directe de l’hyperglycémie implique les neurones hypothalamiques dits « high gluco-excited » (HGE). Grâce à des approches pharmacologiques et génétiques, nous mettons en évidence que les canaux redox sensibles Transient Receptor Potential Canonical 3 et 4 (TRPC3/4) sont fondamentaux pour la détection du glucose par les neurones HGE in vitro, la stimulation de la sécrétion d’insuline et la diminution de la prise alimentaire en réponse à l’hyperglycémie cérébrale in vivo. De plus, nos travaux démontrent que les canaux TRPC3 du MBH jouent un rôle clef dans le contrôle de l’homéostasie énergétique. Les travaux de cette thèse permettent de mettre en évidence deux nouveaux mécanismes de détection hypothalamique de l’hyperglycémie : l’un reposant sur l’implication des canaux TRPC3/4 dans les neurones HGE et l’autre proposant les endozépines astrocytaires comme relai du signal « glucose » aux neurones POMCHyperglycemia is detected and integrated by the mediobasal hypothalamus (MBH) which, in turn, inhibits food intake and triggers insulin secretion. The MBH houses specialized glucose-sensitive (GS) neurons, which directly or indirectly modulate their electrical activity in response to changes in glucose level. In a first study, we hypothesized that indirect detection of glucose by MBH GS neurons involves the secretion of endozepine by astrocytes, a gliotransmitter known to inhibit food intake in response to hyperglycemia. The present work shows that endozepines selectively activate anorexigenic MBH pro-opiomelanotortine (POMC) neurons. In the second study, we show that the direct detection of increased glucose level involves hypothalamic glucose-excited (HGE) neurons. Using pharmacological and genetic approaches, we demonstrate that the redox-sensitive Transient Receptor Potential Canonical 3 et 4 (TRPC3/4) channels are involved in MBH HGE response to glucose in vitro and increased insulin secretion and decreased food intake in response to cerebral hyperglycemia in vivo. We also obtained evidences that MBH TRPC3 channel is a critical new player for energy homeostasis. This thesis work identifies two new mechanisms involved in hypothalamic detection of hyperglycemia: the first based on the involvement of TRPC3/4 channels in HGE neurons and the second highlighting the astroglial endozepines as a relay of the “glucose” signal to POMC neurons
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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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Khajavi, Noushafarin [Verfasser]. "Analysis of expression and function of thermo-sensitive transient receptor potential channels in cultivated human conjunctival epithelial and human uveal melanoma cells / Noushafarin Khajavi." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2015. http://d-nb.info/1075757541/34.
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Velez-Ortega, Alejandra C. "TRPA1 CHANNELS IN COCHLEAR SUPPORTING CELLS REGULATE HEARING SENSITIVITY AFTER NOISE EXPOSURE." UKnowledge, 2014. http://uknowledge.uky.edu/physiology_etds/20.
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TRPA1 channels are sensors for noxious stimuli in a subset of nociceptive neurons. TRPA1 channels are also expressed in cells of the mammalian inner ear, but their function in this tissue remains unknown given that Trpa1–/– mice exhibit normal hearing, balance and sensory mechanotransduction. Here we show that non-sensory (supporting) cells of the hearing organ in the cochlea detect tissue damage via the activation of TRPA1 channels and subsequently modulate cochlear amplification through active cellshape changes.
We found that cochlear supporting cells of wild type but not Trpa1–/– mice generate inward currents and robust long-lasting Ca2+ responses after stimulation with TRPA1 agonists. These Ca2+ responses often propagated between different types of supporting cells and were accompanied by prominent tissue displacements. The most prominent shape changes were observed in pillar cells which here we show possess Ca2+-dependent contractile machinery. Increased oxidative stress following acoustic overstimulation leads to the generation of lipid peroxidation byproducts such as 4-hydroxynonenal (4-HNE) that could directly activate TRPA1. Therefore, we exposed mice to mild noise and found a longer-lasting inhibition of cochlear amplification in wild type than in Trpa1–/– mice.
Our results suggest that TRPA1-dependent changes in pillar cell shape can alter the tissue geometry and affect cochlear amplification. We believe this novel mechanism of cochlear regulation may protect or fine-tune the organ of Corti after noise exposure or other cochlear injuries.
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Kawasaki, Brian Takeshi. "Players in the regulation of calcium entry activation of the transient receptor potential channels by src tyrosine kinase and a distinct role for the IP3 receptor c-terminus in store- and receptor-operated calcium entry /." Diss., Restricted to subscribing institutions, 2005. http://proquest.umi.com/pqdweb?did=994232031&sid=9&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Kim, Hong Geun. "The roles of transient receptor potential channels in thermostatic behavior, in thermal acclimation, and in tonic immobility in the red flour beetle, Tribolium castaneum (coleoptera: tenebrionidae)." Diss., Kansas State University, 2014. http://hdl.handle.net/2097/18216.
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Doctor of PhilosophyDepartment of Entomology
David C. Margolies and Yoonseong Park
Organisms are capable of sensing environmental conditions through diverse mechanisms. Transient receptor potential channels (TRPs) are a cation channel family that has been found to function in diverse sensing mechanisms. In this dissertation, I identified the function of several TRPs in thermosensing and mechanosensing in the red flour beetle, Tribolium castaneum. Candidate TRPs were chosen based on homology to TRPs found and studied in Drosophila melanogaster. To identify the function of candidate TRPs in T. castaneum, I suppressed the expression of target genes by RNA interference technique and investigated the phenotype of each treated beetle. Temperature is a major limiting environmental factor for organisms. I tested the function of candidate TRPs in thermotaxis (behavior) and thermal acclimation (physiology). Using bioinformatics approaches, I identified three candidate TRPs – painless, pyrexia, and trpA1 – involved in high temperature sensing. To test thermotactic behavior, I investigated beetle movement on a temperature arena with two separate temperature zones. Thermal acclimation was tested by pre-exposing beetles to either 42 °C for 10 min. When treated with double stranded RNA of TRPA1 (dstrpA1), the thermotactic response of beetles at 39 and 42 °C was reduced when compared to control groups. With pre-exposure at 42 °C, survivorship of dstrpA1-treated beetles significantly increased after one minute exposure at 52 °C compared to beetles that were not pre-exposed. With dspainless treatment, beetles showed lower response to thermal acclimation and lower long-term survivorship. Beetles treated with dspyrexia showed lower recovery after heat treatment without pre-exposure at 42 °C. To identify the function of candidate TRPs in mechanosensing, I evaluated dsRNA treated beetles for survival, walking behavior, and tonic immobility. Treatment with dsnompC and dstrpA5 resulted in failure in eclosion, causing 93 % mortality in both treatments. Survivors in dsnompC showed defects in elytra sclerotization. In dsnanchung and dsinactive treatments, adults showed abnormal walking behavior and reduced walking speed that were likely caused by defects of mechanosensing in folding of the joint between the femur and tibia. For tonic immobility, beetles with dsnanchung, dsinactive, dswaterwitch and dsick2 (insect cytokine 2) treatments showed increased sensitivity to mechanical stimulation leading to tonic immobility.
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Mergler, Stefan [Verfasser]. "Functional expression of temperature-sensitive transient receptor potential channels (TRPs) in cultured human corneal and conjunctival cells : Relevance in the pathophysiology of ocular surface diseases / Stefan Mergler." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2015. http://d-nb.info/1078505403/34.
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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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Chapleau, Christopher Allen. "The developmental functions of BDNF and MECP2 on dendritic and synaptic structure." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2008. https://www.mhsl.uab.edu/dt/2008p/chapleau.pdf.
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Dumesnil, Dennis. "Neurological Responses to a Glucose Diet in Caenorhabditis elegans." Thesis, University of North Texas, 2017. https://digital.library.unt.edu/ark:/67531/metadc1011786/.
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TRPV channels play a role in both mammalian insulin signaling, with TRPV1 expression in pancreatic beta-cells, and in C. elegans insulin-like signaling through expression of OSM-9, OCR-1, and OCR-2 in stress response pathways. In response to a glucose-supplemented diet, C. elegans are know to have sensitivity to anoxic stress, exhibit chemotaxis attraction, and display reduced egg-laying rate. Transcriptome analysis reveals that glucose stimulates nervous system activity with increased transcript levels of genes regulating neurotransmitters. Ciliated sensory neurons are needed for a reduced egg-laying phenotype on a glucose-supplemented diet. Egg-laying rate is not affected when worms graze on glucose-supplemented Delta-PTS OP50 E. coli, which is defective in glucose uptake. This suggests a possible sensory neuron obstruction by exopolysaccharides produced by standard OP50 E. coli on glucose, eliciting a starvation response from the worm and causing reduced egg-laying rate. Glucose chemotaxis is affected in specific TRPV subunit allele mutants: ocr-2(vs29) and osm-9(yz6), serotonin receptor mutants: ser-1(ok345) and mod-1(ok103), and G-alpha protein mutant: gpa-10(pk362). TRPV deletion mutants had no effect on glucose chemotaxis, alluding to the modality role pf TRPV alleles in specific sensory neurons. The role of serotonin in a reduced egg-laying rate with glucose remains unclear.
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Theis, Thomas [Verfasser], and MELITTA [Akademischer Betreuer] SCHACHNER. "Functional roles of transient receptor potential canonical channels and myristoylated alanine-rich protein kinase C substrate as novel interaction partners of the neural cell adhesion molecule NCAM and polysialic acid in Mus musculus (Linnaeus, 1758) / Thomas Theis. Betreuer: Melitta Schachner." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2013. http://d-nb.info/1035503840/34.
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Dantas, Bruna Priscilla Vasconcelos. "O carvacrol reduz a pressão arterial via ativação de canais receptores de potencial transiente em ratos espontaneamente hipertensos." Universidade Federal da Paraíba, 2014. http://tede.biblioteca.ufpb.br:8080/handle/tede/8055.
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
TRP channels have been extensively studied in many physiological and pathological processes involved in blood pressure regulation. Carvacrol is well known to act on TRP channels in the vasculature, however there are no studies of its effects in hypertensive rats. Our aim was to evaluate the contribution of TRP channels in hypertension and evaluate the effects of carvacrol on TRP channels of SHR. In an electrophysiological approach, carvacrol (300 μM) inhibited the barium current, suggesting a reduction of calcium influx through L-type voltage-operated Ca2+ channels. We found that the mRNA expression of the following TRP channels: TRPV1 (p=0.0007), TRPV4 (p=0.0002), TRPM7 (p=0.0091) and TRPM8 (p=0.0008) are decreased and TRPC1 (p=0,02) are increased in SHR compared to control. In aortic rings preparations precontracted with 1 μM of phenylephrine, carvacrol (10-8 - 3x10-4 M) induced vasorelaxation in WKY (pD2 = 4.88 0.09, Emax = 100.73 2.24%, n = 6) and SHR (pD2 = 4.93 0.08, Emax= 110.06 2.07%, n = 6) in the presence of functional endothelium and that effect was not altered after endothelium removal in WKY (pD2 = 5.09 0.08, Emax = 99.60 0.88%, n = 6) and SHR (pD2 = 5.00 0.08, Emax = 101.23 1.96%, n = 6), proposing an endotheliumindependent mechanism. To assess the role of TRP channels, aortic rings were incubated with ruthenium red. In this assay, the vasorelaxant response was not changed in the WKY. On the other hand both potency (p<0.001) and efficacy (p<0.001) were reduced in SHR, suggesting that carvacrol could activate the subtypes TRPV in hypertensive animals. When using magnesium, equally potency (p<0.001) and pharmacological efficacy (p<0.01) were attenuated in both WKY and SHR, suggesting the involvement of TRPM7. In preparations with 2-APB, CPZ and BCTC, the vasorelaxant effect was potentiated (p<0.01) in both WKY and SHR, suggesting the participation of TRPV1, TRPM8 and TRPM7 channels in the vasorelaxant effect induced by carvacrol. Nevertheless, in the presence of capsaicin, the vasodilator effect was attenuated (p<0.001) in both WKY and SHR endorsing a possible action of carvacrol on TRPV1 and TRPV4 channel. In addition, in vivo studies showed that carvacrol produced hypotension and bradycardia in unanesthetized WKY and SHR. In order to address the cardiovascular responses in vivo, we performed experiments using ruthenium red and capsaicin to evaluate the contribution of TRP channels in this effect. Our results suggested an action of carvacrol on TRPV1 and TRPV4, confirming the in vitro assays. In conclusion, these results suggest that the expression of TRPV1, TRPV4, TRPM7 and TRPM8 was reduced and TRPC1 increased in SHR and carvacrol induced a vasorelaxant effect probably by acting on TRPV1, TRPV4, TRPC1, TRPM7 and TRPM8 in SHR. Furthermore, the in vivo effects induced by carvacrol exhibited a hypotensive and bradycardic activity and this effect, at least in part, is due to an activation of TRPV1 and TRPV4 channels in these responses.
Os canais TRP têm sido amplamente estudados, em diversos processos de regulação fisiológico e patológico no sistema cardiovascular. Carvacrol (5-isopropil-2metilfenol) é conhecido por agir na vasculatura ativando ou bloqueando canais TRP, entretanto não há relatos dos seus efeitos em ratos hipertensos. Nosso objetivo foi avaliar o envolvimento dos canais TRP na hipertensão e o papel do carvacrol nos efeitos cardiovasculares em ratos espontaneamente hipertensos. Em ensaios eletrofisiológicos carvacrol (300μM) promoveu inibição das correntes de bário, sugerindo uma inibição do influxo de cálcio por canais de Ca2+ tipo-L. Ao avaliar a expressão do RNAm dos canais TRP em SHR, observamos pela primeira vez que a expressão de TRPV1 (p=0,0007), TRPV4 (p=0,0002), TRPM7 (p=0,0091), TRPM8 (p=0,0008) foram diminuídas e TRPC1 (p=0,02) aumentada. Em anéis de aorta précontraídos com 1 μM de FEN, o carvacrol (10-8 - 3 ₓ 10-4 M) induziu vasorelaxamento em ratos wistar kyoto (WKY) (pD2 = 4,88 0,09, Emáx = 100,73 2,24%, n = 6; pD2 = 5,09 0,08, Emáx = 99,60 0,88%, n = 6) e em ratos espontaneamente hipertensos (SHR) (pD2 = 4,93 0,08, Emáx = 110,06 2,07%, n = 6) na presença e na ausência do endotélio funcional, respectivamente. Para avaliar a participação dos canais TRP, na ausência do endotélio funcional as preparações foram incubadas com vermelho de rutênio, em WKY não houve alteração da resposta, mas em animais SHR tanto sua potência (p<0,001) como sua eficácia (p<0,001) foram diminuídas, sugerindo que carvacrol pode estar agindo em TRPV nos SHR. Ao utilizar magnésio, em WKY e SHR tanto sua potência (p<0,01) quanto sua eficácia (p<0,001) farmacológica foram atenuadas, sugerindo ação sobre o canal TRPM7. Nas preparações com 2-APB, CPZ e BCTC os seus efeitos foram potencializados (p<0,01), sugerindo ação sobre os canais TRPV1, TRPC1, TRPM7 e TRPM8. Já com capsaicina, um ativador de TRPV1, esse efeito foi atenuado (p<0,001) confirmando uma possível ação do carvacrol sobre TRPV1. Nos estudos in vivo, com WKY e SHR não anestesiados, carvacrol produziu hipotensão e bradicardia, onde ao avaliar a ação dos canais TRP em ensaios com vermelho de rutênio e capsaicina pode-se sugerir uma possível ação de carvacrol sobre TRPV1 e TRPV4, diminuindo a pressão arterial, corroborando com os ensaios in vitro. Em conclusão, esses resultados sugerem que os canais TRPV1, TRPV4, TRPM8 e TRPM7 têm sua expressão diminuída e TRPC1 a expressão aumentada em animais SHR e carvacrol induz efeito vasorelaxante provavelmente agindo em TRPV1, TRPV4, TRPC1, TRPM7 e TRPM8 em SHR. Além disso, os efeitos induzidos por carvacrol in vivo mostraram uma atividade hipotensora e bradicárdica e uma possível influencia dos canais TRPV1 e TRPV4 nessas respostas.
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Dantas, Bruna Priscilla Vasconcelos. "Participação dos canaisTRP nos efeitos cardiovasculares induzidos por carvacrol em ratos." Universidade Federal da Paraíba, 2010. http://tede.biblioteca.ufpb.br:8080/handle/tede/6854.
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Previous issue date: 2010-03-11Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
The pharmacological effects of carvacrol, a monoterpenoid phenol, on the cardiovascular system were studied in normotensive rats, using in vivo and in vitro techniques. In superior mesenteric artery rings isolated from rats with functional endothelium carvacrol (10-8 - 3 ₓ 10-4 M) concentration-dependently relaxed phenylephrine-induced contractions (pD2 = 4.59 0.02, MR = 103.03 1.5%, N=8) and this effect was not altered after removal of the endothelium (pD2 = 4.36 0.02, MR = 111.03 4.8%, N=8), suggesting that the vasorelaxant response induced by carvacrol appears to be independent of vascular endothelium. Furthermore, carvacrol antagonized the vasoconstriction induced by high K+ solution (Tyrode with 80 mM of KCl) (pD2 = 4.12 0.01, MR = 94.38 3.97%, N=6), inhibited contraction elicited by CaCl2 in depolarizing (KCL 60 mM) nominally without Ca2+ medium out carvacrol also antagonized the contractions induced by the L-type Ca2+ channel agonist, S(-)-Bay K 8644 (pD2 = 4.537 0.023, MR = 9.8 3.58%, N=6), indicating that the vasodilatation involve probably the inhibition of Ca2+ influx through L-type voltage-dependent calcium channels (Cav type-L). Additionally, carvacrol antagonized the contractions induced by CaCl2 in nominally without Ca2+ medium in the presence of PHE and nifedipine, suggesting a possible inhibition of calcium influx by store operated channels (SOC), receptor operated channels (ROC) and/or TRP channels. Interestingly, in a depolarizing (KCL 60 mM) nominally without Ca2+ medium and in the presence of nifedipine, carvacrol also inhibited the contraction induced by CaCl2, suggesting a probable inhibition of SOC and/or TRP channels. To evaluate the involvement of TRP channels in the vasorelaxant effect induced by carvacrol, non-selective inhibitors were used. No change in the relaxation response was observed in the presence of ruthenium red (pD2= 4.31 0.029, N=6), however, the effect induced by carvacrol was potentiated by La3+ (pD2 = 5.231 0,04, N=6), Gd3+ (pD2 = 4.97 0.02, N=6) or Ni2+ (pD2 = 5.079 0.02, N=6), furthermore, Mg2+ (pD2 = 4.168 0.021; MR = 81.12 4.03%, N=6) attenuated the relaxation elicited by carvacrol, suggesting that monoterpenoid may to action on TRPC1, TRPC3, TRPC6 and TRPM7 channels. Carvacrol also induced hypotension and bradycardia in non-anesthetized normotensive rats. In conclusion, these results suggest that carvacrol induced vasorelaxant effect in superior mesenteric artery rats isolated probably inhibiting Ca2+ influx by Cav, SOC (TRPC1), ROC (TRPC1 or TRPC6) and TRPM7 channels. Moreover, the effects induced by carvacrol in normotensive non-anesthetized rats showed a hypotensive and bradycardic activity.
Os efeitos farmacológicos de carvacrol, um fenol monoterpenóide, sobre o sistema cardiovascular, foi estudado em ratos normotensos, usando técnicas in vivo e in vitro. Carvacrol (10-8 - 3 ₓ 10-4 M) induziu vasorelaxamento dos anéis de artéria mesentérica superior isolada de rato pré-contraídos com 10 μM FEN (pD2 = 4,59 0,02, Emáx = 103,03 1,5%) na presença do endotélio funcional e esse efeito não foi alterado após a remoção do endotélio (pD2 = 4,36 0,02, Emáx = 111,03 4,8%), sugerindo, portanto, que a resposta vasorelaxante induzida por carvacrol parece ser independente do endotélio vascular. Interessantemente em anéis pré-contraídos com KCl 80 mM (pD2 = 4,12 0,01, Emáx = 94,38 3,97%), observou-se uma diminuição na sua potência e na sua eficácia farmacológica, sugerindo um passo comum na via que seria um aumento citosólico dos níveis de cálcio. Adicionalmente, carvacrol antagonizou, de maneira dependente de concentração, as contrações induzidas por CaCl2 em meio despolarizante nominalmente sem Ca2+ e induziu relaxamento das contrações induzidas pelo S(-)-Bay K 8644 (pD2 = 4,537 0,023, Emáx = 91,8 3,58%) com uma diminuição na sua eficácia farmacológica, sugerindo uma inibição do influxo de cálcio por canais de Ca2+ tipo-L. Além disso, antagonizou as contrações induzidas por CaCl2 em meio nominalmente sem cálcio, na presença de FEN e nifedipina, sugerindo uma provável inibição do influxo de cálcio por SOC, ROC e/ou canais TRP. Como também, em um meio despolarizante e nominalmente sem cálcio na presença de nifedipina esse mesmo antagonismo foi observado, ressaltando a provável inibição dos SOC e/ou canais TRP. Para avaliar a participação dos canais TRP, as preparações foram incubadas com La3+ (pD2 = 5,231 0,04) , Gd3+ (pD2 = 4,97 0,02) e Ni2+ (pD2 = 5,079 0,02) onde seu efeito foi potencializado sugerindo sua ação sobre os canais TRPC e ao utilizar magnésio (pD2 = 4,168 0,021 e Emáx = 81,12 4,03%) tanto sua potência quanto sua eficácia farmacológica foi atenuada, sugerindo inibição do canal TRPM7. Nos estudos in vivo, em ratos normotensos não anestesiados, carvacrol produziu hipotensão e bradicardia. Em conclusão, esses resultados sugerem que carvacrol induz efeito vasorelaxante em anéis de artéria mesentérica superior isolada de rato por inibir provavelmente TRPM7, como também inibir o influxo de cálcio por Cav, SOC, ROC e ou TRPC1 e 6. Além disso, os efeitos induzidos por carvacrol em ratos normotensos não anestesiados mostrou uma atividade hipotensora e bradicárdica.
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Shamsaldeen, Yousif. "Endothelial TRPV4 dysfunction in a streptozotocin-diabetic Rat Model." Thesis, University of Hertfordshire, 2016. http://hdl.handle.net/2299/17622.
Full textAbstract:
Diabetes mellitus is a complex disease characterised by chronic hyperglycaemia due to compromised insulin synthesis and secretion, or decreased tissue sensitivity to insulin, if not all three conditions. Endothelial dysfunction is a common complication in diabetes in which endothelium-dependent vasodilation is impaired. The aim of this study was to examine the involvement of TRPV4 in diabetes endothelial dysfunction. Male Charles River Wistar rats (350-450 g) were injected with 65mg/kg streptozotocin (STZ) intraperitoneally. STZ-injected rats were compared with naïve rats (not injected with STZ) or control rats (injected with 10ml/kg of 20mM citrate buffer, pH 4.0-4.5), if not both. Rats with blood glucose concentrations greater than 16mmol/L were considered to be diabetic. As the results revealed, STZ-diabetic rats showed significant endothelial dysfunction characterised by impaired muscarinic-induced vasodilation, as well as significant impairment in TRPV4-induced vasodilation in aortic rings and mesenteric arteries. Furthermore, STZ-diabetic primary aortic endothelial cells (ECs) showed a significant reduction in TRPV4-induced intracellular calcium ([Ca2+]i) elevation. TRPV4, endothelial nitric oxide synthase (eNOS), and caveolin-1 (CAV-1) were also significantly downregulated in STZ-diabetic primary aortic ECs and were later significantly restored by in vitro insulin treatment. Methylglyoxal (MGO) was significantly elevated in STZ-diabetic rat serum, and nondiabetic aortic rings incubated with MGO (100μM) for 12 hours showed significant endothelial dysfunction. Moreover, nondiabetic primary aortic ECs treated with MGO (100μM) for 5 days showed significant TRPV4 downregulation and significant suppression of 4-α-PDD-induced [Ca2+]i elevation, which was later restored by L-arginine (100μM) co-incubation. Incubating nondiabetic aortic rings with MGO (100μM) for 2 hours induced a spontaneous loss of noradrenaline-induced contractility persistence. Moreover, MGO induced significant [Ca2+]i elevation in Chinese hamster ovary cells expressing rat TRPM8 channels (rTRPM8), which was significantly inhibited by AMTB (1-5μM). Taken together, TRPV4, CAV-1, and eNOS can form a functional complex that is downregulated in STZ-diabetic aortic ECs and restored by insulin treatment. MGO elevation might furthermore contribute to diabetes endothelial dysfunction and TRPV4 downregulation. By contrast, MGO induced the loss of contractility persistence, possibly due to MGO's acting as a TRPM8 agonist.
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Bent, Russell. "Transient Receptor Potential Melastatin 7 Channels Regulate Neuronal Cytoskeletal Dynamics." Thesis, 2011. http://hdl.handle.net/1807/30181.
Full textAbstract:
Transient Receptor Potential ‘Melastatin’ 7 (TRPM7) is a ubiquitously expressed, non-selective divalent cation channel implicated in diverse cellular functions including actomyosin cytoskeletal remodeling, magnesium homeostasis, and anoxic neuronal death. The present study investigates the role of TRPM7 in modulating neuronal morphology and regulating neuronal cytoskeletal dynamics after anoxia. Overexpression of GFP-tagged TRPM7 in neuronal cultures caused a stunted morphology with fewer neurite branches than controls, suggesting that TRPM7 regulates the neuronal cytoskeleton during dendritic outgrowth. I have discovered that TRPM7 may regulate morphology via activation of cofilin-1 (an actin binding protein). I found that TRPM7-dependent cofilin activation during anoxia mediated neuronal death. Overall my work reveals a novel link between anoxia-induced TRPM7 activity and cofilin activation, which likely contributes to neurodegeneration after ischemia.
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Chan, Chan. "The Protein Interactions and Functions of Transient Receptor Potential Melastatin 7 (TRPM7) Ion Channel." Thesis, 2009. http://hdl.handle.net/1807/18245.
Full textAbstract:
Ion channels are proteins that facilitate ion diffusion across cell membrane.
Nevertheless, various groups of ion channels can act as surface receptors and play
important roles in signal transduction. Transient Receptor Potential Melastatin 7
(TRPM7) ion channel has been implicated in diverse cellular functions including
actomyosin cytoskeletal remodeling and anoxic neuronal death. However the
mechanisms behind TRPM7’s physiological roles remain undetermined. TRPM7
possesses unusually long intracellular domains and a functional C-terminal alpha kinase
domain that may contribute to regulation of channel activity and signal transduction. We
therefore identified proteins that interact with TRPM7 C-terminus. Pull-down assays
coupled with LC-MS/MS revealed that cytoskeletal proteins (actin and tubulin) and
synaptic vesicle proteins (VAMP2 and SNAP25) associate with the TRPM7. In addition,
we further found that TRPM7 does not directly bind microtubules or single dimeric
tubulin subunits. Thus one or more microtubule binding proteins is involved in the association between TRPM7 and microtubules.
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Chen, Wenchun. "Studies on the role of calcium channels and the kinase domain of transient receptor potential melastatin-like 7 (TRPM7) in platelet function." Doctoral thesis, 2014. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-103719.
Full textAbstract:
Platelet activation and aggregation are essential processes for the sealing of injured vessel walls and preventing blood loss. Under pathological conditions, however, platelet aggregation can lead to uncontrolled thrombus formation, resulting in irreversible vessel occlusion. Therefore, precise regulation of platelet activation is required to ensure efficient platelet plug formation and wound sealing but also to prevent uncontrolled thrombus formation. Rapid elevations in the intracellular levels of cations are a core signaling event during platelet activation. In this thesis, the roles of Ca2+ and Mg2+ channels in the regulation of platelet function were investigated. Orai1, the major store-operated calcium (SOC) channel in platelets, is not only vital for diverse signaling pathways, but may also regulate receptor-operated calcium entry (ROCE). The coupling between the Orai1 signalosome and canonical transient receptor potential channel (TRPC) isoforms has been suggested as an essential step in the activation of store-operated calcium entry (SOCE) and ROCE in human platelets. However, the functional significance of the biochemical interaction between Orai and TRPC isoforms still remains to be answered. In the first part of this thesis, the functional crosstalk between Orai1 and TRPC6 was addressed. Orai1-mediated SOCE was found to enhance the activity of phospholipases (PL) C and D, to increase diacylglycerol (DAG) production and finally to regulate TRPC6-mediated ROCE via DAG, indicating that the regulation of TRPC6 channel activity seems to be independent of the physical interaction with Orai1. Furthermore, Orai1 and TRPC6 double deficiency led to a reduced Ca2+ store content and basal cytoplasmic Ca2+ concentrations, but surprisingly also enhanced ATP secretion, which may enhance Ca2+ influx via P2X1 and compensate for the severe Ca2+ deficits seen in double mutant platelets. In addition, Orai1 and TRPC6 were not essential for G protein-coupled receptor (GPCR)-mediated platelet activation, aggregation and thrombus formation. Transient receptor potential melastatin-like 7 (TRPM7) contains a cytosolic serine/threonine protein kinase. To date, a few in vitro substrates of the TRPM7 kinase have been identified, however, the physiological role of the kinase remains unknown. In the second part of this thesis, mice with a point mutation which blocks the catalytic activity of the TRPM7 kinase (Trpm7KI) were used to study the role of the TRPM7 kinase in platelet function. In Trpm7KI platelets phosphatidylinositol-4,5-bisphosphate (PIP2) metabolism and Ca2+ mobilization were severely impaired upon glycoprotein (GP) VI activation, indicating that the TRPM7 kinase regulates PLC function. This signaling defect in Trpm7KI platelets resulted in impaired aggregate formation under flow and protected animals from arterial thrombosis and ischemic brain infarction. Altogether, these results highlight the kinase domain of TRPM7 as a pivotal signaling moiety implicated in the pathogenesis of thrombosis and cerebrovascular eventsDie Aktivierung und Aggregation von Thrombozyten sind zwei elementare Prozesse für das Abdichten verletzter Gefäßwände und damit zur Verhinderung von exzessivem Blutverlust. Unter pathologischen Bedingungen kann die Thrombozytenaggregation jedoch zur unkontrollierten Thrombusbildung und folglich zum irreversiblen Gefäßverschluss führen. Daher ist eine präzise Regulation der Thrombozytenaktivierung wichtig, um effizient Gefäßverletzungen zu schließen aber gleichzeitig eine unkontrollierte Thrombusbildung zu verhindern. Schnelle Veränderungen der zytoplasmatischen Konztentration von Kationen stellen ein Kernelement der Signaltransduktion während der Plättchenaktivierung dar. In dieser Arbeit wurden die Rolle von Ca2+ und Mg2+ Kanälen in der Regulation der Thrombozytenfunktion untersucht. Orai1, der bedeutendste store-operated calcium (SOC) Kanal in Thrombozyten, ist nicht nur entscheidend für verschiedene Signalwege, sondern reguliert möglicherweise auch receptor-operated calcium entry (ROCE). Die Kopplung zwischen dem Orai1-Signalkomplex und canonical transient receptor potential channel (TRPC) Isoformen wurde als entscheidender Schritt in der Aktivierung in der Aktivierung von store-operated calcium entry (SOCE) und ROCE in humanen Thrombozyten vermutet. Die Frage nach der funktionellen Relevanz der Interaktion zwischen Orai und TRPC Isoformen blieb jedoch unbeantwortet. Im ersten Teil dieser Arbeit wurde der funktionelle Crosstalk zwischen Orai1 und TRPC6 adressiert. Hierbei zeigte sich, das Orai1-vermittelter SOCE die Aktivität der Phosholipasen (PL) C und D steigert, die Diacylglycerol (DAG) Produktion verstärkt und schließlich TRPC6-vermittelten ROCE via DAG reguliert, was darauf hindeutet, dass die Regulation der TRPC6 Kanalaktivität unabhängig von einer direkten Interaktion mit Orai1 zu sein scheint. Darüber hinaus führte die Doppeldefizienz von Orai1 und TRPC6 zu verringerten Ca2+ Konzentrationen in intrazellulären Ca2+-Speichern und im Zytoplasma der Thrombozyten. Überraschenderweise war auch die ATP-Sekretion erhöht, was eventuell den Ca2+-Einstrom durch P2X1 verstärkt und möglicherweise das starke Ca2+-Defizit in den doppeldefizienten Thrombozyten kompensiert. Außerdem wurde gezeigt, dass Orai1 und TRPC6 nicht für die Aktivierung und Aggregation von Thrombozyten sowie für die Thrombusbildung mittlels G protein-gekoppelter Rezeptoren (GPCR) benötigt werden. Transient receptor potential melastatin-like 7 (TRPM7) enthält eine zytosolische Serin/Threonin-Kinase Domain. Bislang wurden zwar wenige in vitro Substrate der TRPM7 Kinase identifiziert, jedoch ist die physiologische Rolle dieser Kinase immer noch unbekannt. Im zweiten Teil dieser Arbeit wurden Mäuse mit einer Punktmutation, welche die katalytische Aktivität der TRPM7 Kinase blockiert (Trpm7KI) eingesetzt um die Rolle der TRPM7 Kinase für die Funktion von Thrombozyten zu untersuchen. In Trpm7KI Thrombozyten war der Metabolismus von phosphatidylinositol-4,5-bisphosphat (PIP2) und die Ca2+-Mobilisierung nach Aktivierung des Rezeptors Glykoprotein (GP) VI schwer beeinträchtigt, was darauf hindeutet, dass die Aktivität der TRPM7 Kinase die Funktion der PLC reguliert. Aus diesem Signaltransduktionsdefekt in Trpm7KI Thrombozyten resultierte eine verringerte Aggregatbildung unter Flussbedingungen und ein Schutz der Tiere vor arteriellen Thrombosen und ischämischem Schlaganfall. Zusammenfassend heben diese Ergebnisse die Kinasedomäne von TRPM7 als einen ausschlaggebenden Bestandteil in Signalkaskaden hervor und implizieren eine Rolle dieser Domäne in der Pathogenese von ischämischen Kardio- und zerebrovaskulären Erkrankungen