Pregnenolone Sulphate- and Cholesterol-Regulated TRPM3 Channels Coupled to Vascular Smooth Muscle Secretion and Contraction
Jacqueline Naylor,Jing Li,Carol J. Milligan,Fanning Zeng,Piruthivi Sukumar,Bing Hou,Alicia Sedo,Nadira Yuldasheva,Yasser Majeed,Dhananjay Beri,Shan Jiang,Victoria A.L. Seymour,Lynn McKeown,Bhaskar Kumar,Christian Harteneck,David J. O'Regan,Stephen B. Wheatcroft,Mark T. Kearney,Clare A. Jones,Karen E. Porter,David J. Beech +20 more
TLDR
The data suggest functional relevance of TRPM3 in contractile and proliferating phenotypes of vascular smooth muscle cells, significance of constitutive channel activity, regulation by cholesterol, and potential value of pregnenolone sulfate in therapeutic vascular modulation.Abstract:
Rationale: Transient receptor potential melastatin (TRPM)3 is a calcium-permeable ion channel activated by the neurosteroid pregnenolone sulfate and positively coupled to insulin secretion in β cells. Although vascular TRPM3 mRNA has been reported, there is no knowledge of TRPM3 protein or its regulation and function in the cardiovascular system. Objective: To determine the relevance and regulation of TRPM3 in vascular biology. Methods and Results: TRPM3 expression was detected at mRNA and protein levels in contractile and proliferating vascular smooth muscle cells. Calcium entry evoked by pregnenolone sulfate or sphingosine was suppressed by TRPM3 blocking antibody or knock-down of TRPM3 by RNA interference. Low-level constitutive TRPM3 activity was also detected. In proliferating cells, channel activity was coupled negatively to interleukin-6 secretion via a calcium-dependent mechanism. In freshly isolated aorta, TRPM3 positively modulated contractile responses independently of L-type calcium channels. Concentrations of pregnenolone sulfate required to evoke responses were higher than the known plasma concentrations of the steroids, leading to a screen for other stimulators. β-Cyclodextrin was one of few stimulators of TRPM3, revealing the channels to be partially suppressed by endogenous cholesterol, the precursor of pregnenolone. Elevation of cholesterol further suppressed channel activity and loading with cholesterol to generate foam cells precluded observation of TRPM3 activity. Conclusions: The data suggest functional relevance of TRPM3 in contractile and proliferating phenotypes of vascular smooth muscle cells, significance of constitutive channel activity, regulation by cholesterol, and potential value of pregnenolone sulfate in therapeutic vascular modulation.read more
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Role for miR-204 in human pulmonary arterial hypertension
Audrey Courboulin,Roxane Paulin,Nellie J. Giguère,Nehmé Saksouk,Tanya Perreault,Jolyane Meloche,Eric Paquet,Sabrina Biardel,Steeve Provencher,Jacques Côté,Martin J. Simard,Sébastien Bonnet +11 more
TL;DR: Reduced miR-204 expression facilitates the excessive proliferation and apoptosis resistance of pulmonary artery smooth muscle cells characteristic of human pulmonary arterial hypertension.
Journal ArticleDOI
TRPM3 Is a Nociceptor Channel Involved in the Detection of Noxious Heat
Joris Vriens,Grzegorz Owsianik,Thomas Hofmann,Stephan E. Philipp,Julia Stab,Xiaodi Chen,Melissa Benoit,Fenqin Xue,Annelies Janssens,Sara Kerselaers,Johannes Oberwinkler,Rudi Vennekens,Thomas Gudermann,Bernd Nilius,Thomas Voets +14 more
TL;DR: Evidence is provided that TRPM3 functions as a chemo- and thermosensor in the somatosensory system and an unanticipated role for TR PM3 as a thermosensitive nociceptor channel implicated in the detection of noxious heat is revealed.
Journal ArticleDOI
Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine
Bernd Nilius,Arpad Szallasi +1 more
TL;DR: An overview of the functional properties of mammalian TRP channels is given, their roles in acquired and hereditary diseases are described, and their potential as drug targets for therapeutic intervention is discussed.
Journal ArticleDOI
TRPM3 and miR-204 Establish a Regulatory Circuit that Controls Oncogenic Autophagy in Clear Cell Renal Cell Carcinoma
Daniel Hall,Nicholas G. Cost,Nicholas G. Cost,Shailaja Hegde,Emily Kellner,Olga Mikhaylova,Yiwen Stratton,Birgit Ehmer,William Abplanalp,Raghav Pandey,Jacek Biesiada,Christian Harteneck,David R. Plas,Jarek Meller,Jarek Meller,Jarek Meller,Maria F. Czyzyk-Krzeska,Maria F. Czyzyk-Krzeska +17 more
TL;DR: Using shRNAs, a dominant-negative mutant, and a pharmacologic inhibitor, mefenamic acid (MFA), it is established that the Transient Receptor Potential Melastatin 3 (TRPM3) channel promotes the growth of clear cell renal cell carcinoma (ccRCC) and stimulates MAP1LC3A ( LC3A) and MAP1 LC3B (LC3B) autophagy.
Journal ArticleDOI
Role of TRP channels in the cardiovascular system
TL;DR: An overview of current knowledge concerning the physiological functions of TRP channels in the cardiovascular system and their contributions to cardiovascular diseases is presented.
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Transient Receptor Potential Cation Channels in Disease
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