title: TRPC3 contributes to regulation of cardiac contractility and arrhythmogenesis by dynamic interaction with NCX1.
abstract: OBJECTIVE
  TRPC3 is a non-selective cation channel, which forms a Ca2+ entry pathway involved in cardiac remodelling. Our aim was to analyse acute electrophysiological and contractile consequences of TRPC3 activation in the heart.
  
  
  RESULTS
  We used a murine model of cardiac TRPC3 overexpression and a novel TRPC3 agonist, GSK1702934A, to uncover (patho)physiological functions of TRPC3. GSK1702934A induced a transient, non-selective conductance and prolonged action potentials in TRPC3-overexpressing myocytes but lacked significant electrophysiological effects in wild-type myocytes. GSK1702934A transiently enhanced contractility and evoked arrhythmias in isolated Langendorff hearts from TRPC3-overexpressing but not wild-type mice. Interestingly, pro-arrhythmic effects outlasted TRPC3 current activation, were prevented by enhanced intracellular Ca2+ buffering, and suppressed by the NCX inhibitor 3',4'-dichlorobenzamil hydrochloride. GSK1702934A substantially promoted NCX currents in TRPC3-overexpressing myocytes. The TRPC3-dependent electrophysiologic, pro-arrhythmic, and inotropic actions of GSK1702934A were mimicked by angiotensin II (AngII). Immunocytochemistry demonstrated colocalization of TRPC3 with NCX1 and disruption of local interaction upon channel activation by either GSK1702934A or AngII.
  
  
  CONCLUSIONS
  Cardiac TRPC3 mediates Ca2+ and Na+ entry in proximity of NCX1, thereby elevating cellular Ca2+ levels and contractility. Excessive activation of TRPC3 is associated with transient cellular Ca2+ overload, spatial uncoupling between TRPC3 and NCX1, and arrhythmogenesis. We propose TRPC3-NCX micro/nanodomain communication as determinant of cardiac contractility and susceptibility to arrhythmogenic stimuli.
authors: Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria.
authors: Bernhard
authors: B
authors: Doleschal
authors: Department of Cardiology, Medical University of Graz, Graz, Austria Ludwig Boltzmann Institute of Translational Heart Failure Research, Graz, Austria.
authors: Uwe
authors: U
authors: Primessnig
authors: Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria.
authors: Gerald
authors: G
authors: Wölkart
authors: Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria.
authors: Stefan
authors: S
authors: Wolf
authors: Institute of Biophysics, Medical University of Graz, Harrachgasse 21, Graz 8010, Austria.
authors: Michaela
authors: M
authors: Schernthaner
authors: Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria.
authors: Michaela
authors: M
authors: Lichtenegger
authors: Institute of Chemistry, University of Graz, Graz, Austria Christian Doppler Laboratory for Continuous Flow Chemistry, Institute of Chemistry, University of Graz, Graz, Austria.
authors: Toma N
authors: TN
authors: Glasnov
authors: Institute of Chemistry, University of Graz, Graz, Austria.
authors: C Oliver
authors: CO
authors: Kappe
authors: Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria.
authors: Bernd
authors: B
authors: Mayer
authors: Department of Cardiology, Medical University of Graz, Graz, Austria Ludwig Boltzmann Institute of Translational Heart Failure Research, Graz, Austria.
authors: Gudrun
authors: G
authors: Antoons
authors: Department of Cardiology, Medical University of Graz, Graz, Austria Ludwig Boltzmann Institute of Translational Heart Failure Research, Graz, Austria.
authors: Frank
authors: F
authors: Heinzel
authors: Institute of Biophysics, Medical University of Graz, Harrachgasse 21, Graz 8010, Austria.
authors: Michael
authors: M
authors: Poteser
authors: Ludwig Boltzmann Institute of Translational Heart Failure Research, Graz, Austria Institute of Biophysics, Medical University of Graz, Harrachgasse 21, Graz 8010, Austria klaus.groschner@medunigraz.at.
authors: Klaus
authors: K
authors: Groschner
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000473:pathology / Q000503:physiopathology*; D002118:Calcium / Q000502:physiology; D004195:Disease Models, Animal; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology; D018408:Patch-Clamp Techniques; D015398:Signal Transduction / Q000502:physiology*; D019831:Sodium-Calcium Exchanger / Q000502:physiology*; D050052:TRPC Cation Channels / Q000819:agonists / Q000235:genetics / Q000502:physiology*
chemical_list: C499849:NCX1 protein, mouse; D019831:Sodium-Calcium Exchanger; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D002118:Calcium
keywords: Arrhythmias; Ca2+ handling; Cardiac contractility; NCX1; TRPC3
references: J Mol Cell Cardiol. 2012 Feb;52(2):317-22
references: 21600216
references: Circ Res. 2012 Mar 2;110(5):669-74
references: 22302787
references: Br J Pharmacol. 2012 Oct;167(3):493-504
references: 22509897
references: J Mol Cell Cardiol. 2012 Nov;53(5):657-67
references: 22921230
references: Circulation. 2012 Oct 23;126(17):2051-64
references: 22992321
references: Circ Res. 2013 Jun 21;113(1):16-9
references: 23788503
references: J Biol Chem. 2000 May 19;275(20):15239-45
references: 10809760
references: J Clin Invest. 2000 May;105(10):1395-406
references: 10811847
references: Circ Res. 2000 Oct 13;87(8):690-8
references: 11029405
references: Circulation. 2000 Oct 24;102(17):2137-44
references: 11044433
references: Circ Res. 2000 Oct 27;87(9):774-80
references: 11055981
references: Circulation. 2001 Jan 2;103(1):140-7
references: 11136699
references: Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3322-7
references: 11248077
references: Circulation. 2001 Dec 18;104(25):3097-102
references: 11748107
references: Circulation. 2002 Sep 3;106(10):1288-93
references: 12208807
references: J Biol Chem. 2003 Nov 28;278(48):47842-52
references: 12970363
references: J Biol Chem. 2004 Apr 2;279(14):13696-704
references: 14736881
references: J Gen Physiol. 1992 Dec;100(6):905-32
references: 1484285
references: J Gen Physiol. 1997 Feb;109(2):273-86
references: 9041455
references: Cell. 1998 Apr 17;93(2):215-28
references: 9568714
references: Br J Pharmacol. 1999 Aug;127(8):1846-50
references: 10482915
references: J Clin Invest. 2006 Mar;116(3):623-6
references: 16511595
references: FASEB J. 2006 Aug;20(10):1660-70
references: 16873889
references: J Mol Cell Cardiol. 2007 Mar;42(3):498-507
references: 17174323
references: Ann N Y Acad Sci. 2007 Mar;1099:315-25
references: 17446473
references: PLoS One. 2007;2(8):e802
references: 17726532
references: Circ Res. 2007 Nov 9;101(10):1030-8
references: 17872462
references: Biophys J. 2006 Aug 1;91(3):779-92
references: 16679359
references: J Pharmacol Sci. 2006 Sep;102(1):17-21
references: 16960425
references: J Biol Chem. 2006 Nov 3;281(44):33487-96
references: 16950785
references: EMBO J. 2006 Nov 15;25(22):5305-16
references: 17082763
references: Cardiovasc Res. 2007 Jan 1;73(1):111-9
references: 17129578
references: Am J Physiol Heart Circ Physiol. 2007 Feb;292(2):H874-83
references: 17012351
references: Curr Protoc Protein Sci. 2009 Apr;Chapter 19:Unit19.5
references: 19365789
references: J Mol Cell Cardiol. 2010 Jan;48(1):83-9
references: 19345226
references: Cardiovasc Res. 2010 Jul 1;87(1):50-9
references: 20080988
references: Circ Res. 2011 Jan 21;108(2):265-72
references: 21252153
references: J Mol Cell Cardiol. 2011 Mar;50(3):451-9
references: 21147122
references: Proc Natl Acad Sci U S A. 2011 Jun 28;108(26):10556-61
references: 21653882
references: Biochemistry (Mosc). 2011 Oct;76(10):1140-6
references: 22098239
references: Br J Pharmacol. 2012 Jan;165(2):380-9
references: 21585347
references: Circ Res. 2013 Aug 16;113(5):527-38
references: 23825358
references: Cell Calcium. 2013 Sep;54(3):175-85
references: 23800762
references: Circ Res. 2014 Aug 29;115(6):567-80
references: 25047165
references: Circulation. 2000 Mar 28;101(12):1441-6
references: 10736290