title: Ryanodine receptor sensitivity governs the stability and synchrony of local calcium release during cardiac excitation-contraction coupling.
abstract: Calcium-induced calcium release is the principal mechanism that triggers the cell-wide [Ca(2+)]i transient that activates muscle contraction during cardiac excitation-contraction coupling (ECC). Here, we characterize this process in mouse cardiac myocytes with a novel mathematical action potential (AP) model that incorporates realistic stochastic gating of voltage-dependent L-type calcium (Ca(2+)) channels (LCCs) and sarcoplasmic reticulum (SR) Ca(2+) release channels (the ryanodine receptors, RyR2s). Depolarization of the sarcolemma during an AP stochastically activates the LCCs elevating subspace [Ca(2+)] within each of the cell's 20,000 independent calcium release units (CRUs) to trigger local RyR2 opening and initiate Ca(2+) sparks, the fundamental unit of triggered Ca(2+) release. Synchronization of Ca(2+) sparks during systole depends on the nearly uniform cellular activation of LCCs and the likelihood of local LCC openings triggering local Ca(2+) sparks (ECC fidelity). The detailed design and true SR Ca(2+) pump/leak balance displayed by our model permits investigation of ECC fidelity and Ca(2+) spark fidelity, the balance between visible (Ca(2+) spark) and invisible (Ca(2+) quark/sub-spark) SR Ca(2+) release events. Excess SR Ca(2+) leak is examined as a disease mechanism in the context of "catecholaminergic polymorphic ventricular tachycardia (CPVT)", a Ca(2+)-dependent arrhythmia. We find that that RyR2s (and therefore Ca(2+) sparks) are relatively insensitive to LCC openings across a wide range of membrane potentials; and that key differences exist between Ca(2+) sparks evoked during quiescence, diastole, and systole. The enhanced RyR2 [Ca(2+)]i sensitivity during CPVT leads to increased Ca(2+) spark fidelity resulting in asynchronous systolic Ca(2+) spark activity. It also produces increased diastolic SR Ca(2+) leak with some prolonged Ca(2+) sparks that at times become "metastable" and fail to efficiently terminate. There is a huge margin of safety for stable Ca(2+) handling within the cell and this novel mechanistic model provides insight into the molecular signaling characteristics that help maintain overall Ca(2+) stability even under the conditions of high SR Ca(2+) leak during CPVT. Finally, this model should provide tools for investigators to examine normal and pathological Ca(2+) signaling characteristics in the heart.
authors.affiliation: Center for Biomedical Engineering and Technology & Department of Physiology, University of Maryland, Baltimore, Baltimore, MD, United States.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Wescott
authors.affiliation: Center for Biomedical Engineering and Technology & Department of Physiology, University of Maryland, Baltimore, Baltimore, MD, United States; Molecular Neuroscience Department, George Mason University, Fairfax, VA, United States.
authors.forename: M Saleet
authors.initials: MS
authors.lastname: Jafri
authors.affiliation: Center for Biomedical Engineering and Technology & Department of Physiology, University of Maryland, Baltimore, Baltimore, MD, United States.
authors.forename: W J
authors.initials: WJ
authors.lastname: Lederer
authors.affiliation: Center for Biomedical Engineering and Technology & Department of Physiology, University of Maryland, Baltimore, Baltimore, MD, United States. Electronic address: gswill@umaryland.edu.
authors.forename: George S B
authors.initials: GS
authors.lastname: Williams
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000235:genetics*; D056966:Excitation Contraction Coupling / Q000235:genetics*; D006801:Humans; D051379:Mice; D008962:Models, Theoretical; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D012433:Ryanodine / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000235:genetics / Q000473:pathology
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D002118:Calcium
keywords: Action potential; CPVT; Calcium leak; Computational model; Local-control; Mouse
references.citation: J Clin Invest. 2008 Jun;118(6):2230-45
references.pmid: 18483626
references.citation: Circ Res. 2006 May 12;98(9):1151-8
references.pmid: 16601229
references.citation: Prog Biophys Mol Biol. 2004 Jun-Jul;85(2-3):163-78
references.pmid: 15142742
references.citation: Biophys J. 2007 Apr 1;92(7):2311-28
references.pmid: 17237200
references.citation: Biophys J. 2013 May 21;104(10):2149-59
references.pmid: 23708355
references.citation: J Gen Physiol. 2012 Aug;140(2):93-108
references.pmid: 22851674
references.citation: Circ Res. 2013 Feb 1;112(3):424-31
references.pmid: 23243207
references.citation: J Cardiovasc Electrophysiol. 2006 May;17 Suppl 1:S64-S70
references.pmid: 16686684
references.citation: Circ Res. 1994 Jun;74(6):1097-113
references.pmid: 7514510
references.citation: J Gen Physiol. 1985 Feb;85(2):247-89
references.pmid: 2580043
references.citation: Biophys J. 2011 Sep 21;101(6):1287-96
references.pmid: 21943409
references.citation: Biophys J. 1999 Oct;77(4):1871-84
references.pmid: 10512809
references.citation: Biophys J. 2002 Dec;83(6):2918-45
references.pmid: 12496068
references.citation: Circ Res. 2011 Jan 21;108(2):210-8
references.pmid: 21148431
references.citation: Am J Physiol. 1993 Dec;265(6 Pt 2):H2117-36
references.pmid: 8285252
references.citation: Biophys J. 2004 Nov;87(5):3351-71
references.pmid: 15347581
references.citation: J Mol Cell Cardiol. 2013 Jan;54:98-100
references.pmid: 23123322
references.citation: Heart. 2013 Apr;99(7):497-504
references.pmid: 23390049
references.citation: J Gen Physiol. 2013 Sep;142(3):257-74
references.pmid: 23980195
references.citation: J Clin Invest. 2006 Sep;116(9):2510-20
references.pmid: 16932808
references.citation: BMC Physiol. 2009 Aug 31;9:16
references.pmid: 19715618
references.citation: Biophys J. 2006 Jan 1;90(1):77-91
references.pmid: 16214852
references.citation: J Physiol. 2007 Aug 15;583(Pt 1):251-69
references.pmid: 17627991
references.citation: Circ Res. 1994 Jun;74(6):1071-96
references.pmid: 7514509
references.citation: Biophys J. 1992 Aug;63(2):497-517
references.pmid: 1330031
references.citation: Biophys J. 2004 Sep;87(3):1507-25
references.pmid: 15345532
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22275-80
references.pmid: 20018773
references.citation: Biophys J. 1998 Mar;74(3):1149-68
references.pmid: 9512016
references.citation: Circ Res. 1999 Mar 19;84(5):571-86
references.pmid: 10082479
references.citation: Biophys J. 2014 Sep 16;107(6):1289-301
references.pmid: 25229137
references.citation: Science. 1990 Oct 26;250(4980):565-8
references.pmid: 2173135
references.citation: Am J Physiol Heart Circ Physiol. 2002 Feb;282(2):H516-30
references.pmid: 11788399
references.citation: Biophys J. 2004 Dec;87(6):3723-36
references.pmid: 15465866
references.citation: Biophys J. 2001 Dec;81(6):3029-51
references.pmid: 11720973
references.citation: Biophys J. 1998 Jul;75(1):15-32
references.pmid: 9649364
references.citation: PLoS One. 2013 May 09;8(5):e63141
references.pmid: 23671664
references.citation: J Physiol. 2010 Dec 1;588(Pt 23):4743-57
references.pmid: 20962003
references.citation: J Theor Biol. 2008 Jul 7;253(1):170-88
references.pmid: 18405920
references.citation: J Mol Cell Cardiol. 2010 Oct;49(4):617-24
references.pmid: 20655925
references.citation: Am J Physiol Heart Circ Physiol. 2012 Feb 15;302(4):H934-52
references.pmid: 22081697
references.citation: Am J Physiol Heart Circ Physiol. 2004 Sep;287(3):H1378-403
references.pmid: 15142845
references.citation: Am J Physiol Heart Circ Physiol. 2010 Oct;299(4):H1045-63
references.pmid: 20656884
references.citation: J Physiol. 2012 Sep 15;590(18):4553-69
references.pmid: 22615436
references.citation: J Physiol. 2003 Jan 1;546(Pt 1):5-18
references.pmid: 12509475
references.citation: Prog Biophys Mol Biol. 2006 Jan-Apr;90(1-3):136-50
references.pmid: 16321427
references.citation: J Physiol. 1992 Oct;456:267-84
references.pmid: 1338098
references.citation: Biophys J. 2006 Jul 1;91(1):1-13
references.pmid: 16603500
references.citation: Philos Trans R Soc Lond B Biol Sci. 1985 Jan 10;307(1133):353-98
references.pmid: 2578676
references.citation: Circ Res. 2010 Apr 30;106(8):1413-24
references.pmid: 20224043
references.citation: Biophys J. 2008 Jan 15;94(2):392-410
references.pmid: 18160660
references.citation: Biophys J. 2002 Jul;83(1):59-78
references.pmid: 12080100
references.citation: Circ Res. 2013 Jul 5;113(2):142-52
references.pmid: 23674379
references.citation: Ann N Y Acad Sci. 1998 Sep 16;853:20-30
references.pmid: 10603933
references.citation: Circ Res. 2011 Oct 14;109(9):1055-66
references.pmid: 21921263
references.citation: Circ Res. 2001 Aug 17;89(4):329-35
references.pmid: 11509449
references.citation: J Theor Biol. 2008 Aug 7;253(3):483-99
references.pmid: 18486154
references.citation: Circ Res. 1999 Sep 17;85(6):e7-e16
references.pmid: 10488061
references.citation: Br J Pharmacol. 2003 Aug;139(8):1469-79
references.pmid: 12922934
references.citation: Am J Physiol Heart Circ Physiol. 2007 Dec;293(6):H3480-9
references.pmid: 17933974
references.citation: J Biol Chem. 2003 Nov 28;278(48):47997-8003
references.pmid: 12972422
references.citation: Circ Res. 2008 Aug 1;103(3):298-306
references.pmid: 18583715
references.citation: Biophys J. 2014 Dec 16;107(12):3018-3029
references.pmid: 25517166
references.citation: J Physiol. 1994 Apr 15;476(2):279-93
references.pmid: 8046643
references.citation: J Physiol. 2000 Nov 15;529 Pt 1:139-58
references.pmid: 11080258
references.citation: Circ Res. 1996 Jan;78(1):166-71
references.pmid: 8603501
references.citation: J Gen Physiol. 2013 Aug;142(2):127-36
references.pmid: 23858002
references.citation: Circulation. 2013 Sep 17;128(12):1286-97
references.pmid: 23983250
references.citation: Biophys J. 2011 Jan 19;100(2):322-31
references.pmid: 21244828
references.citation: Mol Pharmacol. 2014 Aug;86(2):222-30
references.pmid: 24867460
references.citation: Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):10479-86
references.pmid: 23759742
references.citation: Proc Natl Acad Sci U S A. 2013 Jun 18;110(25):10312-7
references.pmid: 23733959
references.citation: Biophys J. 1996 Dec;71(6):3477-87
references.pmid: 8968617