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Quallo, Talisia Esme. "Roles of TRPM8 and TRPM3 in sensory transduction." Thesis, King's College London (University of London), 2015. https://kclpure.kcl.ac.uk/portal/en/theses/roles-of-trpm8-and-trpm3-in-sensory-transduction(3f273e84-d8cf-4efb-bbd3-ff455adabe17).html.
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Primary afferent neurons are equipped with sensory transduction channels which allow the conversion of physical and chemical stimuli into electrical signals. TRP channels are a heterogeneous superfamily of largely non-selective cation channels, which have been implicated in a myriad of sensory transduction mechanisms from the detection of temperature to the sensation of touch. Many TRP channels are key targets for the study of pain physiology due to their polymodal activation and expression in small diameter, unmyelinated sensory fibres. The aim of my project was to examine the roles of TRP channels in sensory transduction mechanisms. Three results chapters focusing on three different TRP channels are presented. A novel role for the established cold thermosensor, TRPM8, as a cellular osmosensor was determined. The studies presented establish that TRPM8 is activated by increases in extracellular osmolality and is partially activated at normal physiological osmolalities. Cool temperatures increase the sensitivity of TRPM8 to osmotic stimuli and activation of phospholipase enzymes modulates activation of TRPM8 by hyperosmotic solutions. TRPM8 is expressed within sensory neurons where it functions as the chief detector of increased osmolality in addition to a molecular sensor of cold sensations. The role of TRPM3 as a candidate heat transduction channel is examined. The findings presented demonstrate that recombinantly expressed TRPM3 channels are heat-sensitive and mice lacking functional TRPM3 channels lose a population of heat-activated neurons and have impaired behavioural responses to noxious heat. Moreover, modulation of TRPM3 by intracellular pathways downstream of G-protein coupled receptor activation has been determined. Activation of TRPM3 in sensory neurons is shown to be robustly inhibited by morphine in a predominantly mu-opioid receptor and Gi dependent mechanism. Additionally the role of TRPM3 in several pain states is examined. Finally, this thesis reports on the characterisation of a medium-throughput CGRP release assay for examining activation of TRPA1 natively expressed on the central terminals of dorsal root ganglion neurons. Activation of TRPA1 expressed on spinal cord synaptosomes by a selection of agonists evokes a concentration-dependent release of CGRP which is inhibited by TRPA1 antagonists. The VGCC subtypes important for TRPA1 and depolarisation-induced CGRP release are examined.
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Klumpp, Dominik [Verfasser], and Stephan [Akademischer Betreuer] Huber. "TRPM2- und TRPM8-vermittelte Radioresistenz in malignen Tumoren / Dominik Klumpp ; Betreuer: Stephan Huber." Tübingen : Universitätsbibliothek Tübingen, 2016. http://d-nb.info/1164169416/34.
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Tajino, Koji. "Cutaneous TRPM8 channels are thermostats against cooling." 京都大学 (Kyoto University), 2011. http://hdl.handle.net/2433/142123.
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Proudfoot, Clare W. J. "Analgesia mediated by the TRPM8 cold receptor in neuropathic pain." Thesis, University of Edinburgh, 2007. http://hdl.handle.net/1842/29953.
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To identify novel analgesic strategies for chronic pain, we investigated the phenomenon of analgesia produced by cutaneous cooling. The recent identification of specific cold sensory receptors has allowed, for the first time, investigation of the molecular mechanism underlying cooling-induced analgesia. We have shown that the cold-and-menthol receptor. TRPM8, is critically involved in cooling-induced analgesia. Activation of TRPM8 in a subpopulation of sensory afferents (by either cutaneous or intrathecal application of pharmacological agents or by modest cooling) elicits analgesia in neuropathic and other chronic pain models in rats, and inhibits the characteristic sensitisation of dorsal horn neurons that occurs ipsilateral to nerve injury. This analgesia is abolished following antisense knockdown of the TRPM8 receptor. In contrast, activation of the related putative cold-receptor TRPA1 produces hyperalgesia in naïve and neuropathic rats. TRPM8 expression was observed in small diameter sensory neurons in dorsal root ganglia and on afferent terminals in the spinal cord, with increases in specific subsets of sensory neurons following nerve injury. We further found that the central mechanism of TRPM8-mediated analgesia is mediated through inhibitory Group I/III metabotropic glutamate receptors, and is opioid-independent. These results identify TRPM8 as an essential molecular mediator of cooling-induced analgesia. We propose a novel analgesic axis in which activation of TRPM8-expressing afferents by innocuous cooling or chemical ligands leads to activation of inhibitory Group II/III metabotropic glutamate receptors in the spinal cord, which then exert inhibition over nociceptive inputs. These findings suggest that both TRPM8 and the inhibitory metabotropic glutamate receptors are promising targets for the development of novel analgesics for the treatment of neuropathic pain states.
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Kaiser, Simone. "Identification and characterization of the ion channel TRPM8 in prostate cancer." Doctoral thesis, [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972610359.
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Mak, Stephanie Wai Yin. "Modulation of temperature sensitive ion channels TRPV1 and TRPM8 by Bradykinin." Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611520.
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Farhad, Jahanfar. "Identifying antagonist drugs for TRPM8 ion channel as candidates for repurposing." Doctoral thesis, Università di Siena, 2021. http://hdl.handle.net/11365/1162721.
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Even though it is confirmed that ion channels are at the centre of many diseases, approved drugs are only available for small percentage of these proteins, and yet many pathologically important ion channels like transient receptor potential (TRP) cation channels remain without approved drugs. One reason could be the time-consuming and expensive process in drug discovery. Which has high possibility of failure in any step even after approval and marketing. Therefore, repurposing approved drugs might be considered as a solution and may offer an accelerated procedure in finding new treatments for patients.
For the present research we selected TRPM8 ion channel as a neglected target despite growing number of studies regarding its association with numerous diseases. In this project we have first identified potent antagonists for TRPM8 ion channel among approved drugs, by using mainly the automated patch clamp device IonFlux 16. Such device allowed us to screen blocking potency of drugs against TRPM8 ion channel in time efficient way. Our approach consisted of using ligand-based virtual screening method, to optimize our screening by identifying candidates for further screening. We also studied possible interactions of identified drugs with antagonist binding site on TRPM8 channel by molecular docking. Furthermore, we have evaluated the effects of identified antagonists against different types of pancreatic ductal adenocarcinoma (PDAC) cells.
We were able to identify four drugs with IC50 lower than 50 µM including propranolol, propafenone, carvedilol and nebivolol. Among them nebivolol with IC50 = 0.97± 0.15 µM and carvedilol with IC50 = 9.1 ± 0.6 µM were the most potent blockers. Studying the interactions of identified drugs with known binding site of TRPM8 by molecular docking, revealed high possibility of direct binding of nebivolol to binding site of TRPM8. Nebivolol was the most cytotoxic drug against PDACs, but it was also toxic against non-cancerous HEK-293 cells. While carvedilol had cytotoxic against PDACs, interestingly it wasn’t cytotoxic against HEK-293 cells.
Result of these study will provide promising candidates for drug repurposing and will propose promising lead compound in drug discovery for new antagonists of TRPM8 ion channel. Also, our method of approach for identifying candidate drugs as agonist or antagonist could be applied for other ion channels.
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Dias, MarÃlia Leite. "Atividade antinociceptiva da riparina IV: participaÃÃo dos receptores TRPV1, TRPM8, receptores glutamatÃrgicos e do Ãxido nÃtrico." Universidade Federal do CearÃ, 2012. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=8632.
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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel SuperiorA Riparina IV, uma alcamida sintetizada de Aniba riparia, foi testada em modelos animais padronizados de dor, bem como os possÃveis mecanismos de aÃÃo envolvidos. Foram utilizados camundongos Swiss (20-30g), e a Riparina IV foi administrada de forma aguda em todos os testes, nas doses de 25 e 50 mg/kg, por via oral. Foram utilizados os testes de contorÃÃes abdominais induzidas por Ãcido acÃtico; placa quente; teste da formalina; hipernocicepÃÃo mecÃnica induzida pela carragenina; teste da nocicepÃÃo induzida por capsaicina, cinamaldeÃdo, mentol; teste da nocicepÃÃo induzida por glutamato, bem como em modelos comportamentais que permitam excluir a possibilidade de uma atividade relaxante muscular ou induzir resultados falso-positivos nos modelos anteriores, tais como testes do campo aberto e rota Rod. Os resultados demonstraram que a Riparina IV possui uma atividade antinociceptiva no modelo de nocicepÃÃo visceral induzida por Ãcido acÃtico. A Riparina IV nÃo demonstrou atividade no modelo de nocicepÃÃo tÃrmica da placa quente. O prÃ-tratamento com a Riparina IV reduziu significativamente a nocicepÃÃo inflamatÃria induzida pela segunda fase da formalina, porÃm nÃo alterou a nocicepÃÃo neurogÃnica induzida pela primeira fase do teste da formalina. Os animais prÃ-tratados com a Riparina IV tambÃm exibiram uma reduÃÃo significativa na hipernocicepÃÃo mecÃnica induzida pela carragenina. Em relaÃÃo à participaÃÃo dos receptores de potencial transitÃrio (TRP), a Riparina IV demonstrou atividade nos modelos de nocicepÃÃo induzida pela administraÃÃo de capsaicina e mentol, porÃm nÃo apresentou atividade na nocicepÃÃo induzida por cinamaldeÃdo. TambÃm reduziu a nocicepÃÃo induzida pela administraÃÃo intraplantar de glutamato. Para o estudo dos mecanismos de aÃÃo da Riparina IV foi utilizada somente a dose de 50 mg/kg da substÃncia. Na avaliaÃÃo da participaÃÃo dos canais de potÃssio ATP-dependentes, o prÃ-tratamento com glibenclamida nÃo foi capaz de reverter a aÃÃo antinociceptiva da Riparina IV, descartando-se o seu envolvimento; da mesma forma, o prÃ-tratamento com ioimbina, um antagonista α2-adrenÃrgico, e pCPA, um depletor das reservas de serotonina, tambÃm nÃo foram capazes de reverter tal aÃÃo, nÃo havendo envolvimento com o mecanismo de aÃÃo da Riparina IV. O prÃ-tratamento com L-arginina, um precursor do Ãxido nÃtrico, reverteu a aÃÃo antinociceptiva da Riparina IV, sugerindo, em parte, a participaÃÃo da via do Ãxido nÃtrico no seu mecanismo de aÃÃo. Os resultados mostraram que essa substÃncia nÃo alterou a atividade locomotora no teste do campo aberto, nem diminuiu o nÃmero de quedas no teste do rota Rod, descartando a possibilidade de haver sedaÃÃo ou incoordenaÃÃo motora por parte da Riparina IV. Em sÃntese, os resultados demonstraram que a Riparina IV possui uma atividade em modelos animais de nocicepÃÃo, possivelmente envolvendo os receptores TRPV1, TRPM8, glutamatÃrgicos e a via do Ãxido nÃtrico.
Riparin IV, an alkamide synthesized from Aniba riparia, was tested in standard animal models of pain, as well as the possible mechanisms of action involved. It was used Swiss mice (20-30g), and Riparin IV was administred acutely in all tests, at the doses of 25 and 50 mg/kg, by gavage. It was used the tests of abdominal writhing induced by acetic acid, hot plate test, formalin test, mechanical hypernociception induced by carrageenan, nociception test induced by capsaicin, cinnamaldehyde and menthol, nociception test induced by glutamate, as well as models of behavior that ruled out the possibility of a muscle relaxing activity or induce false-positive results in previous models, such as the open field test and the rota Rod test. The results showed that Riparin IV has an antinociceptive activity at the model of visceral nociception induced by acetic acid. Riparin IV did not show any activity at the hot plate thermal nociception model. Pretreatment with Riparin IV reduced significantly the inflammatory nociception induced at the second phase of formalin test, but did not alter the neurogenic nociception induced at the first phase of formalin test. The animals pretreated with Riparin IV also exhibited a significant reduction at the mechanical hypernociception induced by carrageenan. Related to the participation of the Transient Potential Receptors (TRP), Riparin IV showed an activity at the models of nociception induced by capsaicin and menthol, but did not show any activity at the nociception induced by cinnamaldehyde. Also reduced the nociception induced by administration of glutamate at the rind paw. To study the mechanisms of action of Riparin IV, it was used only the dose of 50 mg/kg of the substance. At the evaluation of participation of the ATP-dependent potassium channels, pretreatment with glibenclamide was not able to reverse the antinociceptive action of Riparin IV, discharging its involvment; at the same way, pretreatment with yohimbine, an a2-adrenergic antagonist, and pCPA, a depletor of the serotonin reservations, were not able of reverse such action, not having any involvement with the mechanism of action of Riparin IV. Pretreatment with L-arginine, a precursor of Nitric Oxide, reversed the antinociceptive action of Riparin IV, suggesting, in part, the participation of nitric oxide pathway at the mechanism of action. The results showed that this substance did not alter the locomotor activity at the open field test, neither diminished the number of falls at the rota Rod test, discharging the possibility of sedation or incoordination by Riparin IV. In summary, the results showed that Riparin IV has an action in animal models of nociception, possibly involving the receptors TRPV1, TRPM8, glutamatergic receptors and the nitric oxide pathway.
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Viñuela-Fernández, Ignacio. "Equine laminitis pain and modulatory mechanisms at a potential analgesic target, the TRPM8 ion channel." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/8728.
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Chronic neuropathic pain, resulting from dysfunction of the nervous system, is a clinical concern in both humans and animal patients. Neuropathic pain is characterised by spontaneous pain, hypersensitivity, manifested as hyperalgesia and allodynia, and refractoriness to conventional analgesics such as non-steroidal anti-inflammatory drugs, thus representing an unmet therapeutic need. Equine laminitis is a disease that involves the disruption of the dermoepidermal junction within the hoof, leading to severe pain and lameness, with poor responsiveness to anti-inflammatory therapy. We developed a Quantitative Sensory Testing method, using a novel hydraulically-powered feedbackcontrolled hoof tester, in order to provide an objective tool for the assessment of mechanical hyperalgesia in laminitic horses. Hoof Compression Thresholds of laminitic horses were significantly lower than those of normal horses and variance component analysis of the data confirmed the reliability of the method. In order to investigate mechanisms underlying laminitis pain, we performed histological studies of peripheral nerves innervating the hoof. Electron micrographic analysis of the digital nerve of laminitic horses revealed a significant reduction in the number of unmyelinated and myelinated fibres together with abnormal morphology. Additionally, cell bodies of sensory neurons innervating the hoof in cervical C8 dorsal root ganglia showed an upregulated expression of the nerve injury marker activating transcription factor-3 (ATF3), neuropeptide Y (NPY), and the TRPM8 channel; each of which has been associated with laboratory models of neuropathic pain. Previous work has shown that, in a rodent model of neuropathic pain, the TRPM8 channel is upregulated in sensory neurons and its activation by cool temperature, menthol or icilin leads to reversal of the hypersensitive pain state. Further investigation of TRPM8-channel mediated analgesia was aimed at uncovering the molecular mechanisms involved in the activation of this system in sensitised states. It was hypothesised that serotonin, released following inflammation and nerve damage, can enhance TRPM8 channel activity through peripheral 5-HT1B receptors. Calcium fluorometry carried out in HEK293 cells transfected with the TRPM8 channel and the 5-HT1B receptor revealed that coadministration of a 5-HT1B receptor agonist facilitated the activation of the TRPM8 channel by icilin. Moreover, it appears that this effect is mediated through phospholipase D1 (PLD1), possibly leading to increased production of phosphatidylinositol (4,5-) bisphosphate (PIP2), a known positive modulator of TRPM8 channel activity. In vitro co-immunoprecipitation studies suggested that the TRPM8 channel, the 5-HT1B receptor and PLD1 physically interact with each other, further providing a molecular basis for their functional co-operation. Calcium imaging carried out in cultured rat DRG cells showed that the 5-HT1B receptor-mediated enhancement of icilin responses at the TRPM8 channel also occurs in sensory cells and is reversed by inhibition of PLD1. Moreover, TRPM8 and the 5-HT1B receptor appear to be physically associated in vivo as shown by their co-immunoprecipitation from spinal cord homogenates. Assessment of nociceptive behavioural reflexes following intrathecal injection of selective pharmacological agents provided further support for the idea of 5-HT1B receptor facilitation of TRPM8 channel responses in vivo. In addition to providing novel evidence of a neuropathic component to equine laminitis and validation of a novel QST method for pain assessment in horses, this study reveals for the first time a physical and functional interaction between the 5-HT1B receptor and the TRPM8 channel.
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Bidaux, Gabriel. "Caractérisation du canal calcique TRPM8 dans la physiopathologie de la prostate humaine." Lille 1, 2006. https://pepite-depot.univ-lille.fr/LIBRE/Th_Num/2006/50376-2006-Bidaux.pdf.
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Seconde cause de mortalité par cancer chez l'individu de sexe masculin, le cancer de la prostate présente une incidence croissante liée à l'augmentation de l'espérance de vie dans les pays développés. Les variations pathologiques d'homéostasie calcique sont connues pour participer à l'évolution du cancer de la prostate. Cette thèse porte sur l'étude du canal ionique TRPM8 dont l'expression est spécifique de la prostate et augmente dans les cellules cancéreuses. Nos résultats montrent que l'expression de TRPM8 est finement régulée par le récepteur aux androgènes dans les cellules épithéliales apicales de la prostate et que son apparition coïncide avec la différenciation terminale de ces cellules. Nous démontrons que le canal est fonctionnel dans le plasmalemme des cellules épithéliales apicales, mais aussi dans la membrane du réticulum endoplasmique. Finalement, en corrélant ces travaux avec d'autres réalisés sur des cellules cancéreuses de la prostate, nous avons proposé un modèle d'évolution de l'activité du canal TRPM8 au cours de la différenciation et de l'oncogenèse des cellules de la prostate. Nous avons, d'autre part, mis en évidence l'existence d'isoformes de TRPM8 dont certaines sont des canaux ioniques fonctionnels alors que d'autres sont des petites protéines tronquées agissant comme sous-unités régulatrices du canal TRPM8. Pour finir, nous avons caractérisé une voie d'activation du canal TRPM8 par la phospholipase A2 indépendante du calcium et nous avons réalisé une étude pharmacologique démontrant l'activation de TRPM8 par une classe de molécules dérivées de l'iciline.
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Bidaux, Gabriel Prevarskaya Natalia. "Caractérisation du canal calcique TRPM8 dans la physiopathologie de la prostate humaine." Villeneuve d'Ascq : Université des sciences et technologies de Lille, 2008. https://iris.univ-lille1.fr/dspace/handle/1908/1143.
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Reproduction de : Thèse de doctorat : Biologie-Santé : Lille 1 : 2006.N° d'ordre (Lille 1) : 3912. Articles en anglais, reproduits et intégrés au texte. Résumé en français et en anglais. Titre provenant de la page de titre du document numérisé. Bibliogr. p. 310-326. Liste des publications.
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Winking, Mathis [Verfasser]. "Funktionelle Kooperation der Transmembransegmente S3 und S4 beim Schaltverhalten von TRPM8 / Mathis Winking." Aachen : Hochschulbibliothek der Rheinisch-Westfälischen Technischen Hochschule Aachen, 2015. http://d-nb.info/107668503X/34.
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Molina, Raya Lorena 1979. "Atención en la disfagia orofaríngea en la ancianidad y en pacientes con enfermedades neurológicas." Doctoral thesis, Universitat Pompeu Fabra, 2017. http://hdl.handle.net/10803/664355.
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Resumen de la Tesis DoctoralIntroducción: La disfagia orofaríngea (DO) es muy prevalente en ancianos y pacientes con enfermedades neurológicas. No existe tratamiento farmacológico.Metodología: Se ha realizado una revisión sistemática, un ensayo clínico aleatorizado y un estudio de casos y controles. Resultados: el 66.7% de los estudios hablan de intervenciones en pacientes con DO secundaria a ICTUS. El 82.05% se realizó en entorno hospitalario y las enfermeras se mencionan en el 49.01% de los artículos. El mentol reduce el tiempo de cierre del vestíbulo laríngeo (VL) de 385 ± 136,2 ms a 340,8 ± 176,4 ms en la primera serie (P = 0,050) y 324,2 ± 130,1 en la segunda serie (P = 0,003). El mentol no cambió la prevalencia de residuos orofaríngeos ni la velocidad del bolo como la goma xantana (2; p<0.001; OR: 0.10 IC95%: 0.03 a 0.031). No hubo efectos adversos.Conclusiones: La DO secundaria a ICTUS es la etiología más identificada en la literatura. El cribado y la valoración son las intervenciones más frecuentes realizadas por los profesionales de enfermería. El tratamiento activo neuro-estimulador es el que modifica la biomecánica de la deglución y protege la vía aérea.AbstractIntroduction: Oropharyngeal dysphagia (OD) is a common disorder in elderly and in patients with neurological diseases. There is still not treatment available. Methods: A systematic review, a clinical trial and a case and controls study have been performed. Results: A 66.7% of the studies talk about interventions in patients with OD secondary to ICTUS. An 82.05% of those interventions were performed in a hospital setting and nurses played active role in the interventions in 49.01% of the articles. A 59.66% were experimental studies. Menthol reduced the laryngeal vestibule (LV) closing time from 385(SD:136,2)ms to 340,08(SD:176,4)ms (p=0,050) in the first, and 324,2ms(SD:130,1)ms in the second series (P=0,003). Menthol did not change the prevalence of oropharyngeal residues or bolus velocity as the xanthan-gum (OR: 0.10 IC95%: 0.03-0.031, 2; p<0.001). No adverse effects were detected.Conclusions: OD related to Stroke is the most frequent etiology identity in literature and screening and assessment are the most frequent interventions performed by nursing professionals. The active neuro-stimulator treatment modifies the biomechanics of swallowing, reduces the LV closing time and protect the airway
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Drews, Anna-Dorothée [Verfasser], and Johannes [Akademischer Betreuer] Oberwinkler. "Elektrophysiologische Charakterisierung der murinen Ionenkanäle TRPM1 und TRPM3 und des TRPM Kanals von Drosophila melanogaster / Anna-Dorothée Drews. Betreuer: Johannes Oberwinkler." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2011. http://d-nb.info/1051095492/34.
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Sarria, Ignacio. "Molecular mechanisms and regulation of cold sensing." University of Cincinnati / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1331842901.
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Bavencoffe, Alexis. "Étude des mécanismes de modulation du canal cationique TRPM8 : implication dans la physiopathologie sensorielle et prostatique." Thesis, Lille 1, 2009. http://www.theses.fr/2009LIL10154/document.
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Le canal TRPM8 a été mis en évidence en tant que récepteur au froid au sein des neurones sensoriels des ganglions rachidiens dorsaux (DRG) et trigéminaux. Il est activé par le froid (<28°C) ainsi que par des molécules au pouvoir réfrigérant (menthol, iciline ou eucalyptol). Au niveau périphérique, ce canal est détecté, en outre, au niveau des cellules épithéliales prostatiques saines et cancéreuses. Si plusieurs travaux se sont attachés à déterminer ses modes d’activation, au début de cette thèse, aucune équipe ne s’était intéressée à rechercher des modulateurs physiologiques de ce canal, autres que le froid, aussi bien au niveau sensoriel que prostatique. Partant du constat que la thermosensation se voit altérée au cours de certaines situations physiologique (stress, traitements hormonaux, âge et sexe), nous avons étudié une possible régulation de ce récepteur au froid par les voies de signalisation empruntées par certains neuromodulateurs et hormones.Nos résultats mettent en évidence trois nouvelles voies de régulation de TRPM8 mettant en jeu les androgènes, les agonistes des récepteurs muscariniques et alpha2A adrénergiques. Nos données se confirment au sein des cellules épithéliales prostatiques et des neurones sensoriels. Ces travaux nous permettent d’avancer une possible explication des variabilités inter-individuelles ainsi que des différences due l’âge, au sexe ou face à des situations de stress vis-à-vis de la perception du froid. Enfin, nos résultats nous permettent également de proposer des pistes pour l’établissement de nouvelles stratégies thérapeutiques pour des pathologies associant le canal TRPM8 telles que l’allodynie au froid et le cancer de la prostateTRPM8 is known as a cold receptor expressed in the subset of dorsal root ganglion (DRG) and trigeminal (TG) sensory neurons which are activated by cooling temperatures (<28°C) or by chemical imitators of cooling sensation (menthol, icilin and eucalyptol). While screening for a new marker of prostate carcinoma, Larisa Tsavaler et al. detected TRPM8 channel expression in normal and cancer prostate epithelial cells. Expression of trpm8 gene is androgeno-dependent and change during cancer development. Even though many studies investigated the role of TRPM8 as a cold receptor and described its activation mechanisms, at the beginning of this work no research team had published any information about TRPM8 physiological modulators other than cold, be it in prostate or sensory neurons. Since several works reported modifications of thermosensation during physiological situations such as stress, hormonal therapy, age and gender, we investigated a possible regulation of the cold receptor by neuromodulators, hormones and their signalization pathways. Our results demonstrate three new regulatory mechanisms for TRPM8 involving respectively a new non genomic androgenic, a muscarinic or an alpha2A adrenergic receptors pathway.Our data are confirmed in two physiological models, epithelial prostate cells and dorsal root ganglia neurons. This work leads us to propose a possible explanation for variations which could be accounted for during stress, gender, as well as inter- and intra-individual disparity in thermosensation. Finally, our results could help establishing new therapeutic strategies for pathologies involving TRPM8 such as cold allodynia and prostate cancer
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Dias, Marília Leite. "Atividade antinociceptiva da riparina IV : participação dos receptores TRPV1, TRPM8, receptores glutamatérgicos e do óxido nítrico." reponame:Repositório Institucional da UFC, 2012. http://www.repositorio.ufc.br/handle/riufc/4124.
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DIAS, Marília Leite. Atividade antinociceptiva da riparina IV : participação dos receptores TRPV1, TRPM8, receptores glutamatérgicos e do óxido nítrico. 2012. 82 f. Dissertação (Mestrado em farmacologia) - Universidade Federal do Ceará. Faculdade de Medicina, Fortaleza, 2012.Submitted by denise santos (denise.santos@ufc.br) on 2012-11-20T14:00:15Z No. of bitstreams: 1 2012_dis_mldias.pdf: 915164 bytes, checksum: 85a6dc83f8625a1ac6759c3cdc0dde41 (MD5)
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Riparin IV, an alkamide synthesized from Aniba riparia, was tested in standard animal models of pain, as well as the possible mechanisms of action involved. It was used Swiss mice (20-30g), and Riparin IV was administred acutely in all tests, at the doses of 25 and 50 mg/kg, by gavage. It was used the tests of abdominal writhing induced by acetic acid, hot plate test, formalin test, mechanical hypernociception induced by carrageenan, nociception test induced by capsaicin, cinnamaldehyde and menthol, nociception test induced by glutamate, as well as models of behavior that ruled out the possibility of a muscle relaxing activity or induce false-positive results in previous models, such as the open field test and the rota Rod test. The results showed that Riparin IV has an antinociceptive activity at the model of visceral nociception induced by acetic acid. Riparin IV did not show any activity at the hot plate thermal nociception model. Pretreatment with Riparin IV reduced significantly the inflammatory nociception induced at the second phase of formalin test, but did not alter the neurogenic nociception induced at the first phase of formalin test. The animals pretreated with Riparin IV also exhibited a significant reduction at the mechanical hypernociception induced by carrageenan. Related to the participation of the Transient Potential Receptors (TRP), Riparin IV showed an activity at the models of nociception induced by capsaicin and menthol, but did not show any activity at the nociception induced by cinnamaldehyde. Also reduced the nociception induced by administration of glutamate at the rind paw. To study the mechanisms of action of Riparin IV, it was used only the dose of 50 mg/kg of the substance. At the evaluation of participation of the ATP-dependent potassium channels, pretreatment with glibenclamide was not able to reverse the antinociceptive action of Riparin IV, discharging its involvment; at the same way, pretreatment with yohimbine, an a2-adrenergic antagonist, and pCPA, a depletor of the serotonin reservations, were not able of reverse such action, not having any involvement with the mechanism of action of Riparin IV. Pretreatment with L-arginine, a precursor of Nitric Oxide, reversed the antinociceptive action of Riparin IV, suggesting, in part, the participation of nitric oxide pathway at the mechanism of action. The results showed that this substance did not alter the locomotor activity at the open field test, neither diminished the number of falls at the rota Rod test, discharging the possibility of sedation or incoordination by Riparin IV. In summary, the results showed that Riparin IV has an action in animal models of nociception, possibly involving the receptors TRPV1, TRPM8, glutamatergic receptors and the nitric oxide pathway.
A Riparina IV, uma alcamida sintetizada de Aniba riparia, foi testada em modelos animais padronizados de dor, bem como os possíveis mecanismos de ação envolvidos. Foram utilizados camundongos Swiss (20-30g), e a Riparina IV foi administrada de forma aguda em todos os testes, nas doses de 25 e 50 mg/kg, por via oral. Foram utilizados os testes de contorções abdominais induzidas por ácido acético; placa quente; teste da formalina; hipernocicepção mecânica induzida pela carragenina; teste da nocicepção induzida por capsaicina, cinamaldeído, mentol; teste da nocicepção induzida por glutamato, bem como em modelos comportamentais que permitam excluir a possibilidade de uma atividade relaxante muscular ou induzir resultados falso-positivos nos modelos anteriores, tais como testes do campo aberto e rota Rod. Os resultados demonstraram que a Riparina IV possui uma atividade antinociceptiva no modelo de nocicepção visceral induzida por ácido acético. A Riparina IV não demonstrou atividade no modelo de nocicepção térmica da placa quente. O pré-tratamento com a Riparina IV reduziu significativamente a nocicepção inflamatória induzida pela segunda fase da formalina, porém não alterou a nocicepção neurogênica induzida pela primeira fase do teste da formalina. Os animais pré-tratados com a Riparina IV também exibiram uma redução significativa na hipernocicepção mecânica induzida pela carragenina. Em relação à participação dos receptores de potencial transitório (TRP), a Riparina IV demonstrou atividade nos modelos de nocicepção induzida pela administração de capsaicina e mentol, porém não apresentou atividade na nocicepção induzida por cinamaldeído. Também reduziu a nocicepção induzida pela administração intraplantar de glutamato. Para o estudo dos mecanismos de ação da Riparina IV foi utilizada somente a dose de 50 mg/kg da substância. Na avaliação da participação dos canais de potássio ATP-dependentes, o pré-tratamento com glibenclamida não foi capaz de reverter a ação antinociceptiva da Riparina IV, descartando-se o seu envolvimento; da mesma forma, o pré-tratamento com ioimbina, um antagonista α2-adrenérgico, e pCPA, um depletor das reservas de serotonina, também não foram capazes de reverter tal ação, não havendo envolvimento com o mecanismo de ação da Riparina IV. O pré-tratamento com L-arginina, um precursor do óxido nítrico, reverteu a ação antinociceptiva da Riparina IV, sugerindo, em parte, a participação da via do óxido nítrico no seu mecanismo de ação. Os resultados mostraram que essa substância não alterou a atividade locomotora no teste do campo aberto, nem diminuiu o número de quedas no teste do rota Rod, descartando a possibilidade de haver sedação ou incoordenação motora por parte da Riparina IV. Em síntese, os resultados demonstraram que a Riparina IV possui uma atividade em modelos animais de nocicepção, possivelmente envolvendo os receptores TRPV1, TRPM8, glutamatérgicos e a via do óxido nítrico.
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Klose, Chihab [Verfasser]. "Funktionelle Charakterisierung der Kationenkanäle TRPM3 und Melastatin (TRPM1) / Chihab Klose." Berlin : Freie Universität Berlin, 2012. http://d-nb.info/1029954984/34.
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Grolez, Guillaume. "Rôle et régulation du canal TRPM8 dans la progression et la dissémination métastatique du cancer de la prostate." Thesis, Lille, 2018. http://www.theses.fr/2018LIL1S110.
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Plusieurs études ces dernières décennies suggèrent l’importance des canaux TRPs dont TRPM8 dans le développement et la dissémination du cancer de la prostate. Néanmoins, les différentes études menées sur ce canal sont contradictoires. L’objectif de ma thèse a été d’étudier le rôle précis de TRPM8 dans le cancer prostatique par des études in vivo afin d’évaluer l’impact de TRPM8 sur la croissance tumorale, la dissémination de ces cellules et la formation de métastases. De plus, nous avons approfondi les mécanismes moléculaires sous-jacents régulant l’effet anti-migratoire de TRPM8.Grâce à l’utilisation de nanocapsules lipidiques contenant un agoniste du canal TRPM8, nous avons confirmé par des études in vitro et in vivo un rôle inhibiteur de TRPM8 sur les capacités de migration et d’invasion des cellules cancéreuses prostatiques. De plus, nous avons également déterminer un rôle de TRPM8 sur la croissance tumorale grâce à l’utilisation de greffes orthotopiques dans des prostates murines. Nous avons également déterminé les mécanismes de régulation de la migration cellulaire par le canal TRPM8 et des protéines partenaires à ce canal. Dans ce cadre, nous avons défini et déterminé une régulation du canal TRPM8 par les androgènes modulant la migration cellulaire mais également les mécanismes sous-jacents de l’inhibition de la migration cellulaire induite par TRPM8 et impliquant la petite GTPase Rap1.L’ensemble de nos résultats démontrent un rôle antiprolifératif et anti-migratoire du canal TRPM8 sur les cellule cancéreuses prostatiques, suggérant ainsi une action protectrice de ce canal dans la dissémination des métastases prostatiquesSeveral studies in recent decades suggest the importance of TRP channel including TRPM8 in the development and metastatic dissemination of prostate cancer. Nevertheless, the different studies conducted on this channel are contradictory. The aim of my thesis was to study the precise role of TRPM8 in prostate cancer by in vivo studies to study the impact of TRPM8 on tumor growth and metastatic dissemination. In addition, we determined the underlying molecular mechanisms regulating the anti-migratory effect of TRPM8.Due to the use of lipid nanocapsules containing a TRPM8 channel agonist, we have confirmed by in vitro and in vivo studies an inhibitory role of TRPM8 on the migration and invasion capacities of prostatic cancer cells. In addition, we also determined an inhibitory role of TRPM8 on tumor growth through the use of orthotopic grafts in murine prostates. We also determined the regulatory mechanisms of cell migration by TRPM8 channel and its partner proteins. In this context, we defined and determined a regulation of the TRPM8 channel by androgens modulating cell migration. Moreover, we determined also the mechanisms underlying the inhibition of TRPM8-induced cell migration involving the small Rap1 GTPase.All of my results demonstrate an anti-proliferative and anti-migratory role of the TRPM8 channel on prostatic cancer cells, suggesting a protective action of this channel in the dissemination of prostatic metastases
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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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Skandarani, Nadia. "Développement de nanocapsules lipidiques pour la délivrance de principes actifs." Thesis, Besançon, 2014. http://www.theses.fr/2014BESA2071/document.
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Le développement des nanotechnologies dans le domaine médical a suscité un engouement considérable ces dernières années, notamment l’utilisation de nanoparticules pour la vectorisation de principes actifs. Les nanoparticules offrent des perspectives uniques pour la vectorisation et la délivrance de principes actifs qu’ils soient des gènes (thérapie génique),des anti-cancéreux (chimiothérapie) ou encore des agents photosensibilisateurs (photothérapie dynamique, TPD). Le défi majeur reste cependant l’acheminement des molécules thérapeutiques jusqu’à leur site d’action, tout en gardant leur intégrité ainsi que leur effet thérapeutique.L’axe de recherche de cette thèse est l’utilisation des nanocapsules lipidiques comme plateforme multifonctionnelle pour la délivrance de principes actifs. Un des objectifs étant le développement de nanocapsules lipidiques, stables de point de vue physico-chimique, et fonctionnalisées avec du polyéthylèneimine capables de délivrer efficacement un plasmide ADN et un anti-cancéreux (paclitaxel) dans le cadre d’une thérapie combinée. Les applications de ces nanovecteurs pour la transfectionde gènes et la vectorisation de chimiothérapeutique in vitro ont été réalisées.Par ailleurs, l’aptitude de nanocapsules lipidiques à vectoriser des agents photosensibilisants pour la thérapie photodynamique a été aussi étudiée in vitro, et les résultats ont montré que l’encapsulation de deux molécules de PS dans les nanocapsules permet une synergie de l’effet photodynamique tout en gardant les propriétés physico-chimiques de chaque PS. Enfin, l’encapsulation d’un agoniste au canal ionique TRPM8, le menthol, fait l’objet du dernier chapitre. L’étude par imagerie calcique du relargage de cette molécule lipophile in vitro a permis de confirmer le potentiel des NCL comme nanovecteurs de principes actifsThe development of nanotechnology in the medical field has attracted considerable interest in recent years, including the use of nanoparticles for drug delivery. Nanoparticles offer unique opportunities for delivery of active drugs such as genes (gene therapy), anti-cancer (chemotherapy) or photosensitizers (photodynamic therapy, PDT). The major challenge, however, remains the delivery of therapeutic molecules to their site of action while keeping their integrity and their therapeutic effect.The research focus of this thesis is the use of lipid nanocapsules as a multifunctional platform for the delivery of drugs. One goal is the development of stable lipid nanocapsules, functionalized with polyethyleneimine and capable of effectively delivering a plasmid DNA and an anti-cancer (paclitaxel) as part of a combination therapy. The applications of these nanocarriers for transfection and delivery of chemotherapeutic were performed in vitro.Moreover, the ability of lipid nanocapsules to encapsulate photosensitizers for photodynamic therapy has been studied in vitro, and the results showed that the encapsulation of two molecules of PS in the nanocapsules allows a synergy photodynamic effect while protecting the PS from photo degradation.Finally, encapsulating an ion channel TRPM8 agonist (menthol) is the subject of the last chapter. The study by calcium imaging of the release of this lipophilic molecule in vitro confirmed the potential of lipid nanocapsules as nanocarriers of drugs
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Kaiser, Simone [Verfasser], Matthias [Gutachter] Dürst, Thomas [Gutachter] Börner, and Wolfgang [Gutachter] Kemmner. "Identification and characterization of the ion channel TRPM8 in prostate cancer / Simone Kaiser ; Gutachter: Matthias Dürst, Thomas Börner, Wolfgang Kemmner." Berlin : Humboldt-Universität zu Berlin, 2004. http://d-nb.info/1206182024/34.
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Romero, Amanda Batista da Rocha. "Restrição dietética de magnésio associada à dieta hiperlipídica: implicações sobre a homeostase do mineral e sensibilidade à insulina." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/9/9132/tde-06122018-140629/.
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A resistência dos tecidos à ação da insulina é uma das principais complicações do excesso de peso. O aumento da gordura corporal, decorrente do consumo excessivo de nutrientes, é acompanhado por um quadro de inflamação crônica de baixa intensidade que está relacionado com a fisiopatologia da resistência à insulina. O magnésio (Mg) é um mineral envolvido com diversos processos fisiológicos e bioquímicos, especialmente aqueles relacionados ao metabolismo energético e ao controle glicêmico. Apesar de a deficiência deste mineral estar relacionada com condições pré-diabéticas, não está claro se a inadequação dietética promove alterações na sensibilidade à insulina e/ou se condições de resistência à insulina causam distúrbios na homeostase de Mg. O objetivo deste trabalho foi investigar os efeitos da restrição dietética de Mg e sua associação com o excesso de lipídios sobre a homeostase do mineral e a sensibilidade à insulina. Ratos Wistar, machos, com peso entre 97-123 g, permaneceram em gaiolas individuais por 24 semanas. Os animais receberam rações normolipídicas (CON, 7% de lipídios) ou hiperlipídicas (HL, 32% de lipídios), adequadas (CON e HL Mg; 500 mg de Mg/kg de ração; n = 6 para cada grupo) ou com restrição de Mg (Mg[50] e HL Mg[50]; 50 mg de Mg/kg de ração; n = 6 para cada grupo). O consumo da dieta HL promoveu maior acúmulo de tecido adiposo e maior ganho de peso corporal (p < 0,05). Os animais que consumiram rações com restrição de Mg apresentaram hipomagnesemia (p<0,01), menor excreção urinária (p < 0,01) e fecal (p < 0,001) de Mg e menor concentração óssea desse mineral (p < 0,001). No entanto, não foram observadas alterações no Mg muscular (p > 0,05). O grupo HL Mg[50] apresentou maior concentração de Mg no eritrócito quando comparado aos outros grupos. A restrição dietética de Mg, isoladamente, não promoveu alterações na sensibilidade à insulina (avaliada pelo teste de tolerância à insulina). Quando associada à dieta hiperlipídica, resultou em aumento da glicemia de jejum e em redução da sensibilidade à insulina, após 16 semanas (p < 0,01). Em nível molecular, a fosforilação da proteína quinase B (Akt) no músculo e no fígado foi significantemente menor no grupo HL Mg[50] (p < 0,05). A restrição dietética de Mg induziu ao aumento do conteúdo proteico dos canais TRPM6 e TRPM7 no rim, independentemente da sensibilidade à insulina. Os resultados deste estudo apontam que a deficiência de Mg tende a agravar as repercussões metabólicas do consumo de dietas hiperlipídicas na sensibilidade à insulina e que a resistência à insulina altera a compartimentalização do Mg.Insulin resistance is one of the main complications of overweight. Increase body fat, due to excessive consumption of nutrients is accompanied by a chronic low-grade inflammation related to insulin resistance pathophysiology. Magnesium (Mg) is a mineral involved in many physiological and biochemical processes, especially those related to energy metabolism and glycemic control. Although Mg deficiency is related to pre-diabetic conditions, it is unclear whether dietary inadequacy promotes changes in insulin sensitivity and/or if conditions of insulin resistance cause disturbances in Mg homeostasis. This work aimed to investigate the effects of dietary Mg restriction and its association with high-fat diet on mineral homeostasis and insulin sensitivity. Male Wistar rat (97-123 g) remained in individual cages for 24 weeks. Animals received normolipid diet (CON, 7% lipid) or high-fat diet (HF, 32% lipid), adequate (CON and HF, 500 mg Mg / kg diet, n = 6 for each group) or Mg restricted (Mg[50] and HF Mg[50], 50 mg of Mg / kg of diet, n = 6 for each group). High-fat diet promoted a greater adipose tissue excess and body weight gain (p<0.05). Animals with Mg restricted diet had hypomagnesemia (p<0.01), lower Mg urinary (p<0.01) and faecal loss (p<0.001) and lower bone Mg concentration (p<0.001). However, no changes were observed in muscle Mg (p>0.05). HF Mg[50] group presented higher concentration of erythrocyte Mg when compared to the other groups. Singly, dietary Mg restriction did not induce changes in insulin sensitivity (as assessed by the insulin tolerance test). When associated with high-fat diet, dietary Mg restriction resulted in higher fasting glycemia and lower insulin sensitivity after 16 weeks (p<0.01). At the molecular level, protein kinase B (Akt) phosphorylation in muscle and liver was significantly lower in HFMg [50] group (p<0.05). Dietary Mg restriction induced increased protein content of renal TRPM6 and TRPM7 channels, regardless of insulin sensitivity. The results of this study indicate that Mg deficiency worsens metabolic effects of high-fat diet on insulin sensitivity. In addition, insulin resistance changes Mg compartmentalization.
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Eckstein, Eugenia [Verfasser], and Frank [Akademischer Betreuer] Zufall. "Trpm4 and Trpm5 in the murine olfactory system / Eugenia Eckstein ; Betreuer: Frank Zufall." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2019. http://d-nb.info/1203128940/34.
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Eger, Stephanie [Verfasser], Katharina [Akademischer Betreuer] Zimmermann, and Katharina [Gutachter] Zimmermann. "Vesikel-abhängige TRPM8-Kanalexpression steigert die Kaltsensitivität kutaner C-Fasern im murinen Haut-Nervenpräparat / Stephanie Eger ; Gutachter: Katharina Zimmermann ; Betreuer: Katharina Zimmermann." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2018. http://d-nb.info/1166951103/34.
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Bouvier, Valentine. "La sensibilité au froid des cellules de Merkel et des kératinocytes, leurs contributions à la sensibiblité thermique et tactile de la peau." Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM5071.
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La détection de la température externe par la peau est le point de départ de nombreuses adaptations cellulaires et comportementales permettant de maintenir notre température interne constante. Selon ce concept, les fibres sensorielles cutanées sont les seuls récepteurs sensoriels de la peau pour la détection de la température. Plusieurs canaux ioniques activés directement par des températures chaudes ou froides ont été identifiés, ce sont les canaux TRPs. Le froid peut-il modifier le fonctionnement des organes du toucher?Nous montrons chez l’homme et la souris que les cellules de Merkel (CMs), qui sont les cellules tactiles des complexes de Merkel, peuvent être activées par le froid. Chez les souris dépourvues du canal TRPM8 (KO M8) la réponse au froid des CMs diminue. Le BCTC et le M8B, 2 bloqueurs du canal TRPM8, diminuent également la réponse au froid des CMs. Pour déterminer l’impact de cette sensibilité au froid sur la performance tactile, nous avons enregistré les variations de l’activité nerveuse des récepteurs de Merkel chez les souris WT et KO M8. Un froid modéré (20°C) appliqué sur la peau diminue le train de potentiels d’action issu d’un récepteur de Merkel stimulé mécaniquement. A 20°C ni le seuil de déclenchement des potentiels d’action, ni le train de potentiels d’action en réponse à une stimulation électrique ne sont modifiés. En revanche chez les souris KO M8 cette réponse mécanique tactile n’est plus diminuée. Ce résultat montre pour la première fois qu’une cellule non nerveuse de la peau, la cellule de Merkel, contient un récepteur au froid, le canal TRPM8, qui ajuste l’activité des récepteurs de Merkel lors d’une stimulation tactileIn the skin, Merkel cells (Mcs) are connected to keratinocytes and A sensory nerve fibers and the complexes works as a slow adaptive mechanoreceptor (SA1 receptor). We observe that cooling human and mouse Merkel cells to 15°C increases intracellular Ca2+ ions concentration. The TRPM8 agonist’s provoke intracellular Ca2+ increases. The responses to cooling and TRPM8 agonist’s are reduced in absence of extracellular Ca2+ ions, by the TRPM8 antagonist’s and in KO M8 mouse. These results show that MCs sense cooling through TRPM8 channels. We hypothesize that cooling sensitivity modulate mechano-transduction and we investigate the modulation of SA1 response using the skin nerve and microneurography techniques in mouse and human, respectively. In mouse, cooling the skin at 22°C reduces the frequency of the SA1 discharge, without modifying the nerve conduction. This reduction disappeared in KO M8 mouse. These results suggest that MCs activity reduced the discharge of SA1 receptor at mild fresh temperature, anticipating effect of lower temperature on A nerve fiber excitability.This study is the first report about the sensitivity of MCs to cold temperature and its consequences on the SA1 receptor activity in mouse and human. We conclude that cold sensitivity of Merkel cells mediated by TRPM8 regulates the SA1 mechanical response, particularly at mild fresh temperature, when the nerve conduction is not significantly modified by cold. This is the first description of an active inhibitory process, driven by a TRP channel, during sensory transduction in the skin
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Ferioli, Silvia [Verfasser], and Barbara [Akademischer Betreuer] Conradt. "Cellular functions of the kinase-coupled TRPM6/TRPM7 channels / Silvia Ferioli ; Betreuer: Barbara Conradt." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2018. http://d-nb.info/1162840501/34.
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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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Previous issue date: 2011-02-02Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
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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Hollatz, Dominik [Verfasser], Christian H. R. [Gutachter] Wetzel, and Stefan [Gutachter] Wiese. "Untersuchung der funktionalen und strukturellen Interaktion zwischen TRPM8 und Gq / Dominik Hollatz ; Gutachter: Christian H.R. Wetzel, Stefan Wiese ; Fakultät für Biologie und Biotechnologie." Bochum : Ruhr-Universität Bochum, 2012. http://d-nb.info/1223172031/34.
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Behrendt, Hans-Jörg. "Vergleichende funktionale Untersuchungen des Hitze-Capsaicin-Rezeptors (TRPV1) und des Kälte-Menthol-Rezeptors (TRPM8) in rekombinanten und nativen Zellsystemen (verwendete Spezies: Mensch, Ratte und Maus)." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972279474.
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Ramos-Filho, Antonio Celso Saragossa 1985. "Participação do receptor de potencial transiente vanilóide do tipo 4 (TRPV4) e do melastatina do tipo 8 (TRPM8) nas disfunções miccionais do diabetes em camundongos." [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/312586.
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Orientador: Edson AntunesTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Os receptores TRPV4 e TRPM8 são expressos no urotélio e em fibras aferentes sensitivas da bexiga. Fisiologicamente, a ativação mecânica do receptor TRPV4 na parede da bexiga participa do controle miccional. Em doenças de origem inflamatória, esses receptores adquirem funcionalidade importante. As disfunções da bexiga no diabetes podem estar associadas a alterações ao nível de detrusor, inervação e urotélio. A disfunção urotelial parece ser a responsável por desencadear as alterações neurais e musculares da bexiga. Assim, o objetivo do presente estudo foi investigar os mecanismos fisiopatológicos da ativação dos receptores TRPV4 e TRPM8 no estado diabético em camundongos. Para tanto, dividimos o estudo em duas etapas, sendo que na primeira avaliamos a participação dos receptores TRPV4 e TRPM8 nos mecanismos contráteis e relaxantes do detrusor isolado de animais controles e knockout para esses canais. Em uma segunda etapa estudamos a ativação desses canais em camundongos diabéticos pela injeção intraperitoneal de estreptozotocina (180 mg/Kg) por 4 semanas. Em fragmentos do detrusor isolados de camundongos mostramos que o agonista do receptor TRPV4, GSK1016790A, causou resposta contrátil dependente da concentração. Por outro lado, quando os tecidos foram contraídos com solução despolarizante de KCl, o GSK1016790A causou relaxamento da preparação. No detrusor isolado de animais TRPV4-/- verificamos hipercontratilidade ao carbacol (agonista muscarínico) e à estimulação elétrica, assim como redução no relaxamento ao agonista ?-adrenérgico não-seletivo, isoprenalina. Estes efeitos não foram obtidos com os antagonistas dos receptores TRPV4, RN1734 e HC067047. A indução do diabetes causou nocicepção mecânica e aumento da proporção entre bexiga e peso corpóreo após 4 semanas da injeção. A avaliação miccional dos animais diabéticos mostrou aumento da capacidade, frequência urinária e das contrações involuntárias da bexiga. Observamos ainda hipercontratilidade do detrusor ao carbacol, à estimulação elétrica e ao KCl. A indução do diabetes em animais TRPV4-/- não modificou as disfunções "in vivo" e "in vitro" observadas nos animais wyld type diabéticos, mostrando que a ausência crônica dos receptores TRPV4 desencadeia alterações miccionais que são anteriores as causadas pelo diabetes. Também verificamos que os animais TRPM8-/- não apresentam alteração na resposta contrátil ao carbacol e à estimulação elétrica. Por outro lado, o mentol, mas não a icilina, reduziu significativamente as respostas contráteis nestes animais. O mentol inibiu o influxo de cálcio extracelular em cultura de células da musculatura lisa da bexiga por mecanismo inibitório direto nos canais Cav1.2. O tratamento agudo com mentol, intraperitoneal e intravesical, atenuou as disfunções miccionais observadas nos camundongos diabéticos. "In vitro" o pré-tratamento com mentol reduziu a hipercontratilidade ao carbacol no grupo diabético, sem alterar a resposta no grupo controle. Concluímos que o mentol impede a resposta contrátil da bexiga por mecanismo independente do receptor TRPM8 bloqueando o influxo de cálcio extracelular nos canais Cav1,2, podendo ser utilizado como tratamento na hiperatividade de bexiga de origem miogênica
Abstract: The TRPV4 and TRPM8 receptors are expressed in bladder urothelium and sensitive afferent fibers. Physiologically, the mechanical activation of TRPV4 receptor in the bladder wall is involved in micturition control. In inflammatory diseases, these receptors may have important roles. The bladder dysfunction in diabetes may be associated with changes at the level of detrusor, innervation and urothelium. The urothelial dysfunction triggers neural changes, modifying consequently the smooth muscle contractility. Thus, the goal of the present study was to investigate the pathophysiological mechanisms of TRPV4 and TRPM8 receptor activation in physiological and diabetic conditions in mice. For this purpose we divided the study in two phases, the first of which we evaluated the participation of TRPV4 and TRPM8 receptors in detrusor contractile and relaxing mechanisms in control and knockout animals for these channels. In the second phase we studied the activation of these channels in diabetic mice induced by intraperitoneal injection of streptozotocin (STZ; 180 mg / kg, 4 weeks). The TRPV4 agonist GSK1016790A produced concentration-dependent detrusor contractions. On the other hand, in detrusor pré-contracted with KCl (80 mM), GSK1016790A caused relaxation responses. In TRPV4-/- animals, we verified hypercontractility to carbachol (muscarinic agonist) and electrical-field stimulation, as well as a decreased relaxation to isoprenaline (non-selective ?-adrenergic agonist). These effects were not obtained with the TRPV4 antagonists, RN1734 and HC067047. Induction of diabetes with STZ caused hyperglycemia, mechanical nocicepton, and increased ratio between bladder and body weight after 4 weeks. The miccturition evaluationin diabetic animals showed increased capacity, urinary frequency, and non-voiding contractions. Hypercontractility to carbachol, electrical-field stimulation and KCl in isolated detrusor were lso observed. The induction of diabetes in TRPV4-/- animals did not change the urinary dysfunctions. Our data are consistent with the proposal that TRPV4 receptor has a physiological function in micturition control by decreasing muscarinic-induced contractions and increasing ?-adrenergic-mediated relaxations. Moreover, the bladder contractions to carbachol and EFS in TRPM8-/- did not significantly change compared to TRPM8+/+. However, menthol (300 ?M), but not icilin (1 ?M), significantly inhibited these contractile responses. The menthol (300 ?M) inhibited extracellular calcium influx in bladder smooth muscle cell culture by direct mechanism though Cav1.2 channels. In addition the acute treatment with menthol, intraperitoneal and intravesical, atenuated the micturition dysfunctions observed in diabetic mice. Also, detrusor preparations pre-treated with menthol decreased carbachol hypercontractility, without changing the responses in normoglycemic group. Menthol reduces bladder contractions by mechanisms independent of TRPM8 receptor activation, inhibiting extracellular calcium influx through Cav1.2 channel, thus been considered as treatment for bladder overactivity of myogenic origin
Doutorado
Farmacologia
Doutor em Farmacologia
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Bianchetti, Elena. "Cell death neuroprotection and repair mechanisms in a model of rat spinal cord injury in vitro." Doctoral thesis, SISSA, 2013. http://hdl.handle.net/20.500.11767/4099.
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Nowadays, new spinal cord injury (SCI) cases are frequently due to non traumatic causes, especially vascular disorders. A prerequisite to developing mechanism-based neuroprotective strategies for acute SCI is a full understanding of the early pathophysiological changes to prevent later disability and paralysis. The immediate damage spreads from the initial site through excitotoxicity and metabolic dysfunction (ischemia, free radicals and neuroinflammation) to surrounding tissue (secondary damage). Using an in vitro neonatal rat spinal cord model, an experimental protocol (pathological medium, PM) has been developed to mimic the profound metabolic
perturbation (hypoxia, aglycemia, oxidative stress, acidosis, toxic free radicals) occurring in vivo after ischemic SCI, a condition surprisingly worsened by extracellular Mg2+ (1 mM). The current study sought to identify the cells affected by PM (with Mg2+), and the associated molecular death pathways in the spinal lumbar region which contains the locomotor networks. The results indicated that 1 h PM+Mg2+ application induced delayed pyknosis chiefly in the spinal white matter via overactivation of poly (ADP-ribose) polymerase 1 (PARP1), suggesting cell death mediated by the process of parthanatos and also via caspase 3-dependent apoptosis. Grey matter damage was less intense and concentrated in dorsal horn neurons and motoneurons which became nuclearimmunoreactive for the mitochondrial apoptosis-inducing factor. Moreover, TRPM2 channel expression was enhanced 24 h later in dorsal horn and motoneurons, while TRPM7 channel expression concomitantly decreased. Conversely, TRPM7 expression grew earlier (3 h) in white matter cells, while TRPM2 remained undetectable. Our results show that extracellular Mg2+ amplified the white matter cell death via parthanatos and apoptosis, and motoneuronal degeneration via PARP1-dependent pathways with distinct changes in their TRPM expression. In fact, the PARP-1 inhibitor PJ34, when applied 30 min after the moderate excitotoxic insult, could protect spinal networks controlling locomotion in more than 50 % of preparations. Interestingly, the drug per se strongly increased spontaneous network discharges without cell damage. Glutamate ionotropic receptor blockers suppressed this phenomenon reversibly. Our results suggest that pharmacological inhibition of PARP-1 could prevent damage to the locomotor networks if this procedure had been implemented early after the initial lesion and when the lesion was limited. PJ34 had also a positive effect on PM+Mg2+ treated spinal cords, especially in the white matter after 24 h, both alone or administered together with caspase-3 inhibitor. The neonatal rat in vitro SCI model was also useful to study the activation of endogenous spinal stem cells. We identified the ATF3 transcription factor as a novel dynamic marker for ependymal stem/progenitor cells (nestin, vimentin and SOX2 positive) located around the central canal of the neonatal or adult rat spinal cord. While quiescent ependymal cells showed cytoplasmic ATF3 expression, over 6-24 h in vitro these cells mobilized and acquired intense nuclear ATF3 staining. The migration of ATF3-nuclear positive cells preceded the strong proliferation of ependymal cells occurring after 24 h in vitro. Pharmacological inhibition of MAPK-p38 and JNK/c-Jun, upstream effectors of ATF3 activation, prevented the mobilization of ATF3 nuclear-positive cells. Excitotoxicity or ischemia-like conditions did not enhance migration of ependymal cells at 24 h. ATF3 is, therefore, suggested as a new biomarker of activated migrating stem cells in the rat spinal cord in vitro that represents an advantageous tool to study basic properties of endogenous stem cells.
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Gruschwitz, Philipp [Verfasser], Katharina [Akademischer Betreuer] Zimmermann, Katharina [Gutachter] Zimmermann, and Alexey [Gutachter] Ponomarenko. "Beitrag der beiden Kalttransduktionskanäle TRPM8 und TRPA1 zur Kodierung kalter Temperaturen in mono- und polymodalen C-Fasern der Maus / Philipp Gruschwitz ; Gutachter: Katharina Zimmermann, Alexey Ponomarenko ; Betreuer: Katharina Zimmermann." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2017. http://d-nb.info/1223708187/34.
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Beesetty, Pavani. "Consequences of TRPM7 kinase inactivation in immune cells." Wright State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=wright1526406780596661.
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Roudaut, Yann. "Sensibilité des cellules de Merkel humaines au froid : vers un rôle des complexes de Merkel dans la sensibilité thermique cutanée ?" Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM5016.
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Le rôle des cellules de Merkel dans la sensibilité cutanée reste imprécis. Elles assurent la décharge continue du récepteur de Merkel lors d'une pression sur la peau, mais on ne connait ni les autres stimuli capables de les activer, ni les médiateurs régulant leur activité. Cette ignorance est en partie liée à la difficulté d'isoler ces cellules qui ne représentent que 3 à 5% des cellules de la peau.Dans ce travail nous avons développé une technique de culture des cellules de Merkel à partir de peau humaine, en utilisant un tri cellulaire basé sur l'expression du récepteur CD56. Nous avons alors montré que les cellules de Merkel sont thermosensibles. Leur sensibilité aux températures fraiches est associée au fonctionnement du canal TRPM8. Cette sensibilité thermique ne module pas le fonctionnement du récepteur à une stimulation tactile. En revanche, les contacts entre les fibres cutanées C et Aδ, qui sont connues pour véhiculer les sensations thermiques, et les cellules de Merkel suggèrent que ces récepteurs pourraient intervenir aussi dans la thermosensation. Nous proposons donc pour la première fois que les récepteurs de Merkel soient aussi des récepteurs thermosensibles assurant une détection concordante de la pression et de la température cutanéeThe role of Merkel cells in cutaneous sensitivity remains imprecise. They provide continuous discharge of the receptor to a pressure. Nevertheless, other stimuli able to activate this complex, mediators regulating their activity are unknown. This ignorance is partly related to the difficulty to isolate these cells that represent only 3 to 5 % of skin cells.In this work, we have developed a Merkel cells cultured technique from human skin, using cell sorting based on the expression of the CD56 receptor. In this work, we show that Merkel cells are temperature sensitive. Their cool sensitivity is associated to TRPM8 channel. This thermal sensitivity does not modulate the discharge of the receptors during tactile stimulation. However, contacts between cutaneous Aδ and C fibres, which are known to carry the thermal sensations, and Merkel cells suggest that these receptors may also be involved in thermosensation. We propose for the first time that Merkel receptors are also temperature sensitive receptors providing a concurring detection of cutaneous pressure and temperature
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Miquel, Perrine. "Regulation of TRPM7 by Aldosterone." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=104628.
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ABSTRACTTRPM7 (transient receptor potential melastatin), a member of the large TRP ion channel family, is ubiquitously expressed in cells and is constitutively active. It is comprised of six transmembrane domains that assemble into tetramers to form a central Mg2+ and Ca2+ permeable pore. TRPM7 and its homologue TRPM6 are some of the only channels known to carry Mg2+. Hypertension, a cardiovascular condition linked to low levels of intracellular Mg2+ is also associated with high levels of aldosterone. Previous results have demonstrated that aldosterone increases mRNA levels of TRPM7 whereas protein levels decreased in VSMCs. To understand if TRPM7 may be implicated in hypertension, we questioned whether aldosterone could regulate TRPM7 currents, and inquired for a possible underlying mechanism. Whole-cell patch clamp studies were conducted in inducible HEK-293 cells, stably expressing wild type TRPM7. We found that TRPM7 currents are enhanced after overnight stimulation with aldosterone compared to non-stimulated cells. When the mineralocorticoid receptor (hMR) is transfected two days prior aldosterone stimulation, this response is further increased. The introduction of 10mM BAPTA, a Ca2+ chelator, to the intracellular medium doubled the TRPM7 current in WT cells and also increased the response to aldosterone in cells transfected with the hMR receptor. Surprisingly, protein levels of TRPM7 do not vary, suggesting a redistribution of already existing channels to the membrane. SGK-1, a serine threonine kinase was suggested as a possible mediator of the response. In fact, when a specific blocker to SGK-1 is applied onto the cells, both current and total protein levels of TRPM7 are significantly decreased. Overall, these results demonstrate that aldosterone can regulate TRPM7 through an increase in total current. This response appears to be mediated by SGK-1 in a calcium sensitive manner.RÉSUMÉTRPM7 (transient receptor potential melastatin), membre de la large famille des canaux ioniques des TRP, est exprimée de façon omniprésente dans toutes les cellules, et est active de façon constitutive. TRPM7 est composée de six domaines transmembranaires qui s'assemblent en tétramères pour former un pore central, perméable aux ions Mg2+ et Ca2+. TRPM7, et son homologue TRPM6, sont les seuls canaux ioniques connus pour le transport du Mg2+. L'hypertension, une maladie cardiovasculaire associée à de faibles niveaux en Mg2+ intracellulaire est aussi liée à de niveaux élevés d'aldosterone. Des recherches antérieures ont démontré que l'aldosterone augmente les niveaux d'ARNm de TRPM7 tandis que la quantité de protéines diminue dans les cellules vasculaires lisses du muscle. Afin de comprendre si TRPM7 peut être impliquée dans l'hypertension, nous nous sommes demandés si l'aldosterone pouvait réguler les courants associés à TRPM7, et si nous pouvions définir un mécanisme d'action qui pourrait expliquer une telle régulation. La technique du patch clamp a été utilisée sur des cellules HEK-293 inductibles exprimant de façon stable le phénotype humain de TRPM7. Nous avons trouvé que les courants de TRPM7 sont augmentés après une stimulation de nuit avec de l'aldosterone, comparé à des cellules non stimulées. Lorsque le récepteur humain mineralocorticoid (hMR) est transfecté deux jours avant la stimulation par l'aldosterone, la réponse en courant est rehaussée. L'ajout de 10mM de BAPTA, un chélateur du Ca2+, dans la solution intracellulaire permet de doubler la réponse en courant dans ces cellules, ainsi que d'augmenter la réponse à l'aldosterone dans les cellules transfectées avec le récepteur hMR. Etonnamment, les niveaux de protéines de TRPM7 ne sont pas affectés, suggérant une redistribution des canaux ioniques déjà existants à la membrane. SGK-1, une kinase membre de la famille des serine-threonines a été proposée comme un possible médiateur de la réponse a l'aldosterone. En effet, après l'application d'un bloquer spécifique pour le SGK-1, une diminution des courants ainsi que de la quantité de protéines associées à TRPM7 a été observée. De façon générale, ces résultats démontrent que l'aldosterone est capable de réguler TRPM7 à travers une augmentation des courants. Cette réponse, qui semble être sous l'influence de SGK-1, utilise un mécanisme sensible aux niveaux de calcium intracellulaire..
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Zou, Jie. "Function and modulation of TRPM2 channels." Thesis, University of Leeds, 2013. http://etheses.whiterose.ac.uk/5902/.
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Melastatin-related transient receptor potential 2 (TRPM2) channel is a Ca2+-permeable cation channel that is gated by ADP-ribose (ADPR) and also activated by reactive oxygen species (ROS) such as H2O2. TRPM2 channel are shown to be critically involved in several physiological and pathological cell processes. Previous studies have reported inhibition of the human TRPM2 channel by extracellular acidic pH. However, the underlying mechanism is not fully understood. In the present study, I performed patch-clamp recordings to examine the effect of extracellular acidic pH on ADPR-induced currents in HEK293 cells heterogeneously expressing human TRPM2 (hTRPM2) or mouse TRPM2 (mTRPM2) channels. The results showed that the inhibition was substantially reversible upon brief exposure to acidic pH but became irreversible after prolonged exposure, supporting the mechanism in which protons bind to and inhibit the open TRPM2 channel and the proton-binding induces further conformational changes leading to channel inactivation. Furthermore, the mTRPM2 channel exhibited a lower sensitivity to, and slower kinetics of, inhibition, than the hTRPM2 channel. A residue in the pore region (His-995 in hTRPM2 and Gln-992 in mTRPM2) had a crucial role in determining such species differences. The pharmacology of the TRPM2 channel is poor, with no specific inhibitor. Here, I examined the effects of 48 hit compounds identified from screening chemical libraries on hTRPM2 channels expressed in HEK293 cells. Four compounds inhibited H2O2-induced Ca2+-response with a micromolar to submicromolar potency and abolished ADPR-induced currents at 10 μM, indicating that they act as TRPM2 channel inhibitors. The TRPM2 channel was reported to be functionally expressed in macrophage cells, but its role in mediating ROS-induced Ca2+ signalling and cell death is largely unclear. This study examined the contribution and mechanism of the TRPM2 channel in H2O2-induced Ca2+-responses and cell death in RAW264.7 and differentiated THP-1 macrophage cells and peritoneal macrophage cells isolated from TRPM2+/+ and TRPM2-/- mice. The results showed that TRPM2 channels operated as cell surface Ca2+-permeable channels and constituted the principal Ca2+ signalling mechanism, but played a limited role in cell death. In summary, the results from my study provided useful information to advance the understanding of the pharmacology and functional roles of the TRPM2 channels.
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Decker, Amanda R. "TRPM7 function in zebrafish dopaminergic neurons." Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/5927.
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TRPM7 (Transient Receptor Potential Melastatin-like 7) is an ion channel necessary for the proper development of many cell types. Insight into the precise role of the channel in different cells has been hampered by the lethality of knocking out the gene in model organisms such as the mouse. Here I examine a zebrafish that has a loss-of-function mutation in the gene encoding Trpm7. First, I show that trpm7 is important for the function of developing dopaminergic neurons in the zebrafish. Second, I examine the interaction between trpm7 and the related gene vmat2 in order to develop a cellular mechanism of trpm7 function in presynaptic dopaminergic neurons. Finally, I investigate the necessity of the kinase and ion channel domains of trpm7 in their ability to promote pigmentation in melanophores as a model cell type. Based on the results from these experiments and observations from other researchers, I form a new hypothesis for Trpm7 function in protein sorting. These studies provide a detailed and novel analysis of the function of an ion channel that is necessary for life.
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Georgiev, Plamen. "Functional analysis of Drosophila TRPM." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611931.
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Naylor, Jacqueline. "Function and pharmacology of TRPM3 ion channel." Thesis, University of Leeds, 2008. http://etheses.whiterose.ac.uk/330/.
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For many ion channels there are few, if any, pharmacological agents, and even fewer showing specificity. In this study, a set of pharmacological tools were developed to investigate TRPM3, a widely expressed transient receptor potential (TRP) channel for which no functional role has yet been identified. Human TRPM3 was first expressed in HEK 293 cells and shown to be activated by hypo-osmotic challenge or sphingosine, consistent with previous reports. In addition, TRPM3 was activated by pregnenolone sulphate. Hydrophobicity analysis of the TRPM3 amino acid sequence revealed a short and reasonably unique peptide in the 3rd extracellular loop (E3) region, to which polyclonal antiserum (TM3E3) was produced. Extracellular application of TM3E3 inhibited TRPM3 function with a high degree of specificity, having no effect on TRPM2 or example members of other sub-types of mammalian TRP, TRPC5 or TRPV4. The data validate E3-targeting as an approach for production of isoform-specific channel blockers and reveal a specific agent for blocking TRPM3. The cellular and tissue functions of TRPM3 were also investigated. RT-PCR and immunocytochemistry demonstrated TRPM3 expression in human saphenous vein smooth muscle cells, where sphingosine- and pregnenolone sulphate-induced calcium responses were also apparent. These calcium responses could be selectively blocked by TM3E3. Furthermore, TRPM3 activators inhibited matrix metalloproteinase and interleukin-6 secretion, indicating a protective function for TRPM3 in vascular smooth muscle cells. Medium throughput screening systems were employed to screen a library of compounds for further TRPM3 modulators with vascular relevance. Cholesterol, antidepressants, antipsychotics, calmodulin inhibitors, and PIP2 all inhibited TRPM3, whereas nifedipine and elevated temperature activated the channel. TRPM3 appears to be regulated by a large number of different chemicals and mechanisms. In summary, TRPM3 has constitutive, protective, activity which can be suppressed by a multitude of compounds, including known vascular disease factors such as cholesterol.
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Straub, Isabelle. "Identification and application of novel and selective blockers for the heat-activated cation channel TRPM3." Doctoral thesis, Universitätsbibliothek Leipzig, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-149321.
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TRPM3 (melastatin-related transient receptor potential 3) is a calcium-permeable nonselective cation channel that is expressed in various tissues, including insulin-secreting β-cells and a subset of sensory neurons from trigeminal and dorsal root ganglia (DRG). TRPM3 can be activated by the neurosteroid pregnenolone sulphate (PregS) or heat. TRPM3α2 mice display an impaired sensation of noxious heat and inflammatory thermal hyperalgesia. A calcium-based screening of a compound library identified four natural compounds as TRPM3 blockers. Three of the natural compounds belong to the citrus fruit flavanones (hesperetin, eriodictyol and naringenin), the forth compound is a deoxybenzoin that can be synthesized from an isoflavone of the root of Ononis spinosa (ononetin). The IC50 for the substances ranged from upper nanomolar to lower micromolar concentrations. Electrophysiological whole-cell measurements as well as calcium measurements confirmed the potency of the compounds to block TRPM3 in DRG neurones. To further improve the potency and the selectivity of TRPM3 block and to identify the pharmacophore within the flavanone structure, we conducted a hit optimisation procedure by re-screening a focussed library. The library composed of several flavanones with different substitutions on relevant chemical positions and of representatives from different flavonoid subgroups. Within this secondary screen, we identified isosakuranetin and liquiritigenin as active blockers of PregS-induced Ca2+ entry through TRPM3. Isosakuranetin, a flavanone that can be found in blood oranges and grapefruits, displayed an IC50 of 50 nM, and is the most potent inhibitor of TRPM3 identified so far. The novel compounds exhibited a marked specificity for TRPM3 compared with other thermosensitive TRP channels, and blocked PregS-induced [Ca2+]i signals and ionic currents in freshly isolated DRG neurones. Furthermore, isosakuranetin and hesperetin reduced the sensitivity of mice to noxious heat and PregS-induced chemical pain. Since the physiological functions of TRPM3 channels are still poorly defined, the development and validation of potent and selective blockers is expected to contribute to clarifying the role of TRPM3 in vivo. Considering the involvement of TRPM3 in nociception, TRPM3 blockers may represent a novel concept for analgesic treatment.
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Fernandez, Jose A. "Gating mechanisms of the TRPM* ion channel." Thesis, Queen's University Belfast, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.534741.
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Plesch, Eva Veronika [Verfasser]. "Entwicklung selektiver Aktivatoren für TRPML-Ionenkanäle / Eva Veronika Plesch." München : Verlag Dr. Hut, 2019. http://d-nb.info/1178898326/34.
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Li, Xin. "TRPM2 channel-mediated signalling mechanisms for neuronal cell death." Thesis, University of Leeds, 2017. http://etheses.whiterose.ac.uk/18576/.
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Transient receptor potential melastatin-related 2 (TRPM2) channel is gated by ADP-ribose (ADPR) and potently activated by reactive oxygen species (ROS) through stimulating ADPR-generating mechanisms. Recent studies provide evidence to show a crucial role for TRPM2 in neuronal death and cognitive impairment associated with ischemic stroke and Alzheimer’s disease. However, the underlying mechanisms are poorly understood. Studies described in this thesis adopted genetic and pharmacological interventions, in conjunction with immunofluorescent and live cell imaging, to investigate TRPM2-dependent cell death induced by H2O2 and the 42-residue of amyloid β (Aβ42) in cultured hippocampal neurons. H2O2 and Aβ42 induced significant neuronal death, which was reduced or prevented by TRPM2 knock-out (TRPM2-KO), TRPM2 channel inhibitors, or Zn2+ chelator TPEN. H2O2 and Aβ42 induced intracellular Zn2+ increase, lysosomal dysfunction and Zn2+ release, mitochondrial Zn2+ accumulation, dysfunction and ROS generation. Bafilomycin A1-induced lysosomal dysfunction also resulted in mitochondrial Zn2+ accumulation and ROS generation. These events were abolished by TRPM2-KO or suppressed by inhibiting poly(ADP-ribose) polymerase-1 (PARP-1) or TRPM2 channel. Immunofluorescent imaging suggests mitochondrial localization of TRPM2. ADPR enhanced Zn2+ accumulation in isolated mitochondria from wild-type (WT) but not TRPM2-KO neurons. Finally, the inhibition of protein kinase C (PKC) and NADPH oxidases (NOX), particularly NOX1/4, suppressed H2O2/Aβ42-induced neuronal death and Aβ42-induced intracellular Zn2+ increase, lysosomal and mitochondrial dysfunction, and mitochondrial ROS generation. The inhibition of the proline-rich tyrosine kinase 2 (Pyk2) and the downstream MEK/ERK kinases protected against Aβ42-induced neuronal death. Taken together, these results provide evidence to support a vicious positive feedback signalling loop that drives hippocampal neuronal death in response to ROS and Aβ42, in which the TRPM2 channel in mitochondria integrates multiple mechanisms comprising PKC/NOX-mediated ROS generation, lysosomal dysfunction and Zn2+ release, mitochondrial Zn2+ accumulation, mitochondrial dysfunction and ROS generation. In addition, the Pyk2-MEK-ERK signalling pathway is critically involved in Aβ42-induced TRPM2-dependent neuronal death. These findings provide novel insights into the mechanisms underlying neuronal death and cognitive impairment related to ischemic stroke and AD.
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Barbet, Gaëtan. "Rôle du canal ionique TRPM4 dans les cellules dendritiques." Paris 7, 2009. http://www.theses.fr/2009PA077114.
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Les cellules dendritiques (DC) sont des cellules centrales du système immunitaire. Elles activent les lymphocytes et permettent l'orientation de la réponse immune adaptative. Pour cela, les DC doivent maturer et migrer vers les organes lymphoïdes secondaires, lieus de la mise en place d'une réponse lymphocytaire spécifique de l'agent infectieux. Le calcium est un second messager ubiquitaire régulant de nombreuses fonctions cellulaires dont la migration. Cependant, le rôle du calcium dans la biologie des cellules dendritiques a été relativement peu étudié. Nous montrons que le canal ionique TRPM4 est un acteur majeur de la régulation de l'homéostasie du calcium des DC après activation. En effet, l'absence de TRPM4 dans les DC induit une surcharge calcique après activation bactérienne ce qui affecte fortement la migration des DC sans affecter leur maturation. Nous avons observé qu'une surcharge calcique entraînait une diminution de l'expression de la PLC-p2 ce qui est corrélé à une absence de réponse lors d'une seconde stimulation calcique. Ainsi, ces travaux nous ont permis de montrer que TRPM4 est essentiel à la régulation de la migration et non de la maturation des DC renforçant l'idée selon laquelle ces deux entités biologiques sont régulées différemment. Un substrat artificiel des serines protéine-kinases F a-caséine et une protéine cytoplasmique de poids moléculaire de 65 kDa et de pH isoélectrique de 6,8Dendritic cells (DC) are central cells in immune System. DCs lead to lymphocyte activation and control adaptative immune response. To do so, DCs have to maturate and migrate toward secondary lymphoid organs where they initiate pathogen-specific lymphocyte responses. Calcium is an ubiquitous second messenger controlling a variety of cellular functions such as migration. However, the role of calcium in dendritic cells biology is poorly understood. We show that the ionic channel TRPM4 has a crucial role in calcium homeostasis in DC during stimulation. The lack of TRPM4 in DC leads to calcium overload after bacterial stimulation and dramatically decrease their migratory capacities but without affecting their maturation. We observed that a calcium overload leads to a decrease of the PLC-p2 expression which is correlated with an absence of a subsequent signalling response. Thus, this work shows the key rôle of TRPM4 in the migration but not the maturation of DC, emphasizing that these two cellular events are regulated differently
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Lange, Ingo. "The TRPM2 ion channel in nucleotide-gated calcium signaling." kostenfrei, 2008. http://d-nb.info/989951200/34.
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VENUTO, SANTINA. "Dissecting the TRIM8 role in the pathogenesis of glioma." Doctoral thesis, Università degli Studi di Foggia, 2019. http://hdl.handle.net/11369/382357.
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I gliomi umani sono un gruppo eterogeneo di tumori cerebrali maligni primari, la cui patogenesi molecolare risulta ancora parzialmente sconosciuta. Pertanto, la comprensione dei meccanismi molecolari alla base della loro insorgenza e del loro decorso può portare a una migliore scelta di terapie appropriate e a migliori risultati prognostici, attraverso l'identificazione di nuovi geni specifici associati al glioma. Le proteine appartenenti alla famiglia “tripartite motif” (TRIM) sono coinvolte in diversi processi biologici, tra cui la regolazione trascrizionale, il controllo della progressione del ciclo cellulare, la proliferazione e il differenziamento cellulare. Alterazioni dell’espressione delle proteine TRIM sono associate a una varietà di patologie quali disturbi dello sviluppo, malattie infiammatorie e tumori. Tra le circa 80 proteine identificate appartenenti alla famiglia delle TRIM, TRIM8 è una E3 ubiquitina-ligasi coinvolta in vari processi patologici, quali ipertrofia, risposta antivirale, encefalopatia e sviluppo di diverse forme di cancro. Abbiamo recentemente identificato TRIM8 come un gene differenzialmente espresso nei gliomi, la cui espressione è correlata a un esito clinico sfavorevole nei pazienti con glioma. Per ottenere informazioni approfondite sulle funzioni di TRIM8, ne abbiamo studiato il “trascrittoma” e l' “interattoma” in cellule staminali neurali embrionali di topo, usando l’RNA-Sequencing e la spettrometria di massa, e successivamente analizzando i dati ottenuti mediante programmi bioinformatici. Sono state quindi eseguite analisi funzionali, biochimiche e cellulari, per esplorare il ruolo TRIM8 in differenti processi biologici. Il nostro studio ci ha permesso di identificare vie di segnale correlate alla neurotrasmissione e al sistema nervoso centrale (SNC), fornendo ulteriori prove dell'esistenza di una relazione funzionale tra TRIM8 e STAT3, con possibili implicazioni nello sviluppo e nella progressione del glioma. Abbiamo successivamente dimostrato che TRIM8 interagisce con KIFC1 e KIF11/Eg5, due importanti regolatori dell'assemblaggio del fuso mitotico e della riorganizzazione del citoscheletro. Approfondendo lo studio sul ruolo di TRIM8 nel processo mitotico, abbiamo verificato che TRIM8 localizza a livello del fuso mitotico durante la progressione della mitosi e svolge un ruolo chiave nella separazione dei centrosomi all’inizio della divisione mitotica, con un conseguente ritardo nella progressione della mitosi e un impatto sulla stabilità cromosomica. I nostri risultati confermano il ruolo di TRIM8 nelle funzioni cerebrali attraverso la deregolazione di geni appartenenti al pathway JAK-STAT e coinvolti in diverse funzioni del SNC. Inoltre, abbiamo identificato la funzione fisiologica di TRIM8 nello sviluppo del fuso mitotico, evidenziando un ruolo emergente di TRIM8 nella regolazione della mitosi.Human gliomas are a heterogeneous group of primary malignant brain tumors, whose molecular pathogenesis is not yet solved. Therefore, understanding the molecular mechanisms underlying their aggressive behavior may lead to better management, appropriate therapies, and good outcomes through the identification of novel specific glioma-associated genes. Members of the tripartite motif (TRIM) proteins family are involved in many biological processes, including transcriptional regulation, cell proliferation and differentiation and cell cycle progression. Alterations of TRIM proteins are associated with a variety of pathologies like developmental disorders, inflammatory diseases and cancers. Among TRIMs protein family, TRIM8 encodes an E3 ubiquitin ligase involved in various pathological processes, including hypertrophy, antiviral defense, encephalopathy, and cancer development. We have identified TRIM8 as a gene aberrantly expressed in gliomas, whose expression correlates with unfavorable clinical outcome in glioma patients. To gain insights into the TRIM8 functions, we profiled the TRIM8 transcriptome and interactome in primary mouse embryonic neural stem cells using RNA-sequencing and proteomics, followed by bioinformatics analysis. Functional analysis, including biochemical and cellular assays were then performed to explore TRIM8 roles in different pathways. Our study firstly identified enriched pathways related to the neurotransmission and to the central nervous system (CNS) functions, providing additional evidence about the existence of a functional interactive crosstalk between TRIM8 and STAT3 with possible implications in the development and progression of glioma. Then, we found that TRIM8 interacts with KIFC1 and KIF11/Eg5, two master regulators of mitotic spindle assembly and cytoskeleton reorganization. Exploring the TRIM8 role in the mitotic spindle machinery, we showed that TRIM8 localizes at the mitotic spindle during mitosis and plays a role in centrosome separation at the beginning of mitosis with a subsequent delay of the mitotic progression and impact on chromosomal stability. Our results substantiate the role of TRIM8 in the brain functions through the deregulation of genes involved in different CNS-related pathways, including JAK-STAT. Moreover, we provided insights on the physiological function of TRIM8 in the mitotic spindle machinery, pointing to an emerging role for TRIM8 in the regulation of mitosis
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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.
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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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Xia, Rong. "TRPM2 Channel : Assembly, Ion permeability, and regulation by interacting proteins." Thesis, University of Leeds, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.511157.
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Schäfer, Sebastian [Verfasser], and Thomas [Akademischer Betreuer] Gudermann. "Pharmakologische Beeinflussbarkeit der TRPM7 Kanalkinase / Sebastian Schäfer ; Betreuer: Thomas Gudermann." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1182899749/34.
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