Activation of Transient Receptor Potential Canonical 3 (TRPC3)-mediated Ca2+ Entry by A1 Adenosine Receptor in Cardiomyocytes Disturbs Atrioventricular Conduction

Sabourin, Jessica; Antigny, Fabrice; Robin, Eric; Frieden, Maud; Raddatz, Eric

doi:10.1074/jbc.m112.378588

Cited by 30 publications

(27 citation statements)

References 70 publications

(62 reference statements)

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“…Hence, to our knowledge, the current study is the first demonstration of GPCR- An alternative mechanism for A1 adenosine receptor-induced Ca 2+ influx is via storeoperated Ca 2+ channels. Interestingly, the A1 adenosine receptor promotes receptoroperated Ca 2+ entry in cardiomyocytes via a phospholipase C and PKC-dependent pathway [48]. Although beyond the scope of the present study, it would be of interest to investigate the mechanism(s) underlying A1 adenosine receptor-induced Ca 2+ influx in H9c2 cells.…”

Section: In Vitro Modulation Of Tg2 By the A1 Adenosine Receptormentioning

confidence: 91%

A1 adenosine receptor-induced phosphorylation and modulation of transglutaminase 2 activity in H9c2 cells: A role in cell survival

Vyas

Hargreaves

Bonner

et al. 2016

Biochemical Pharmacology

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The regulation of tissue transglutaminase (TG2) activity by the GPCR family is poorly understood. In this study, we investigated the modulation of TG2 activity by the A1 adenosine receptor in cardiomyocyte-like H9c2 cells.H9c2 cells were lysed following stimulation with the A1 adenosine receptor agonist N 6 -cyclopentyladenosine (CPA).Transglutaminase activity was determined using an amine incorporating and a protein cross linking assay. TG2 phosphorylation was assessed via immunoprecipitation and 3

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Section: In Vitro Modulation Of Tg2 By the A1 Adenosine Receptormentioning

confidence: 91%

A1 adenosine receptor-induced phosphorylation and modulation of transglutaminase 2 activity in H9c2 cells: A role in cell survival

Vyas

Hargreaves

Bonner

et al. 2016

Biochemical Pharmacology

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“…9). A possible interpretation is that such a QTp normalization in H6 hearts by ADO could be associated with the subtle increase of calcium entry in cardiomyocytes through L-type Ca 2ϩ and/or TRPCs channels via A 1 AR activation as we recently demonstrated in the same experimental model (40,43).…”

Section: Adenosine Was Cardioprotective During Anoxiareoxygenationmentioning

confidence: 97%

A hypoxic episode during cardiogenesis downregulates the adenosinergic system and alters the myocardial anoxic tolerance

Robin

Marcillac

Raddatz

2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Robin E, Marcillac F, Raddatz E. A hypoxic episode during cardiogenesis downregulates the adenosinergic system and alters the myocardial anoxic tolerance. Am J Physiol Regul Integr Comp Physiol 308: R614 -R626, 2015. First published January 28, 2015 doi:10.1152/ajpregu.00423.2014.-To what extent hypoxia alters the adenosine (ADO) system and impacts on cardiac function during embryogenesis is not known. Ectonucleoside triphosphate diphosphohydrolase (CD39), ecto-5=-nucleotidase (CD73), adenosine kinase (AdK), adenosine deaminase (ADA), equilibrative (ENT1,3,4), and concentrative (CNT3) transporters and ADO receptors A 1, A2A, A2B, and A3 constitute the adenosinergic system. During the first 4 days of development chick embryos were exposed in ovo to normoxia followed or not followed by 6 h hypoxia. ADO and glycogen content and mRNA expression of the genes were determined in the atria, ventricle, and outflow tract of the normoxic (N) and hypoxic (H) hearts. Electrocardiogram and ventricular shortening of the N and H hearts were recorded ex vivo throughout anoxia/reoxygenation Ϯ ADO. Under basal conditions, CD39, CD73, ADK, ADA, ENT1,3,4, CNT3, and ADO receptors were differentially expressed in the atria, ventricle, and outflow tract. In H hearts ADO level doubled, glycogen decreased, and mRNA expression of all the investigated genes was downregulated by hypoxia, except for A 2A and A3 receptors. The most rapid and marked downregulation was found for ADA in atria. H hearts were arrhythmic and more vulnerable to anoxia-reoxygenation than N hearts. Despite downregulation of the genes, exposure of isolated hearts to ADO 1) preserved glycogen through activation of A1 receptor and Akt-GSK3␤-GS pathway, 2) prolonged activity and improved conduction under anoxia, and 3) restored QT interval in H hearts. Thus hypoxia-induced downregulation of the adenosinergic system can be regarded as a coping response, limiting the detrimental accumulation of ADO without interfering with ADO signaling.anoxia-reoxygenation; arrhythmias; glycogen metabolism; hypoxia; adenosine signaling LOW OXYGEN LEVEL is a prerequisite for normal embryonic and fetal growth including the cardiovascular system. However, hypoxia-induced imbalance between O 2 supply and demand impacts gene expression, metabolism, growth, and function (13,17,20,21,33,45,48,50,53,56). Oxygen deprivation during critical periods of embryogenesis impairs heart development and function with hemodynamic disturbances resulting in fetal growth retardation and increasing the risk of cardiovascular disease in adulthood, the so-called "fetal programming" (8,12,26,38,47,57,59). Maternal hypoxemia, reduction in umbilical blood flow, or placental insufficiency can rapidly lead to acute or chronic ischemia and/or hypoxia, which exacerbates ATP-derived adenosine (ADO) production. Since ADO represents an important regulator of the embryonic cardiovascular function (35), the present study focuses on the modulation of the adenosinergic system by hypoxia and its functional consequences in the d...

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“…[40][41][42][43] When ERK inhibitors were used, cells were treated after 3 days of culture for 24 hours with 50 mM PD98059 or 10 mM U0126 (Tocris Bioscience). Sixteen cultures from eight rats were performed for each condition.…”

Section: Cell Culture Treatmentsmentioning

confidence: 99%

“…[33][34][35] TRPC3 also promotes cardiac hypertrophy through calcineurin and NF of activated T cells [36][37][38][39] and mediates a proarrhythmic Ca 2+ entry in cardiac myocytes. 40,41 The TRPC3-selective inhibitor, ethyl-1-(4-(2,3,3-trichloroacrylamide)phenyl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylate (pyr3), is reported to block cardiac hypertrophy in mice subjected to pressure overload, with a marked selectivity for TRPC3 over other TRPs from the same family, 42 and prevent stentinduced arterial remodeling. 43 More recently, TRPC3 has been found in human cardiac fibroblasts and regulated cell proliferation and differentiation in atrial fibrillation.…”

mentioning

confidence: 99%

Evidence of a Role for Fibroblast Transient Receptor Potential Canonical 3 Ca2+ Channel in Renal Fibrosis

Saliba¹,

Karam²,

Smayra

et al. 2015

Journal of the American Society of Nephrology

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Transient receptor potential canonical (TRPC) Ca 2+ -permeant channels, especially TRPC3, are increasingly implicated in cardiorenal diseases. We studied the possible role of fibroblast TRPC3 in the development of renal fibrosis. In vitro, a macromolecular complex formed by TRPC1/TRPC3/TRPC6 existed in isolated cultured rat renal fibroblasts. However, specific blockade of TRPC3 with the pharmacologic inhibitor pyr3 was sufficient to inhibit both angiotensin II-and 1-oleoyl-2-acetyl-sn-glycerol-induced Ca 2+ entry in these cells, which was detected by fura-2 Ca 2+ imaging. TRPC3 blockade or Ca 2+ removal inhibited fibroblast proliferation and myofibroblast differentiation by suppressing the phosphorylation of extracellular signalregulated kinase (ERK1/2). In addition, pyr3 inhibited fibrosis and inflammation-associated markers in a noncytotoxic manner. Furthermore, TRPC3 knockdown by siRNA confirmed these pharmacologic findings. In adult male Wistar rats or wild-type mice subjected to unilateral ureteral obstruction, TRPC3 expression increased in the fibroblasts of obstructed kidneys and was associated with increased Ca 2+ entry, ERK1/2 phosphorylation, and fibroblast proliferation. Both TRPC3 blockade in rats and TRPC3 knockout in mice inhibited ERK1/2 phosphorylation and fibroblast activation as well as myofibroblast differentiation and extracellular matrix remodeling in obstructed kidneys, thus ameliorating tubulointerstitial damage and renal fibrosis. In conclusion, TRPC3 channels are present in renal fibroblasts and control fibroblast proliferation, differentiation, and activation through Ca 2+ -mediated ERK signaling. TRPC3 channels might constitute important therapeutic targets for improving renal remodeling in kidney disease.

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Activation of Transient Receptor Potential Canonical 3 (TRPC3)-mediated Ca2+ Entry by A1 Adenosine Receptor in Cardiomyocytes Disturbs Atrioventricular Conduction

Cited by 30 publications

References 70 publications

A1 adenosine receptor-induced phosphorylation and modulation of transglutaminase 2 activity in H9c2 cells: A role in cell survival

A1 adenosine receptor-induced phosphorylation and modulation of transglutaminase 2 activity in H9c2 cells: A role in cell survival

A hypoxic episode during cardiogenesis downregulates the adenosinergic system and alters the myocardial anoxic tolerance

Evidence of a Role for Fibroblast Transient Receptor Potential Canonical 3 Ca2+ Channel in Renal Fibrosis

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