title: Recovery of cardiac calcium release is controlled by sarcoplasmic reticulum refilling and ryanodine receptor sensitivity.
abstract: OBJECTIVE
  In heart cells, the mechanisms underlying refractoriness of the elementary units of sarcoplasmic reticulum (SR) Ca(2+) release, Ca(2+) sparks, remain unclear. We investigated local recovery of SR Ca(2+) release using experimental measurements and mathematical modelling.
  
  
  RESULTS
  Repeated Ca(2+) sparks were induced from individual clusters of ryanodine receptors (RyRs) in quiescent rat ventricular myocytes, and we examined how changes in RyR gating influenced the time-dependent recovery of Ca(2+) spark amplitude and triggering probability. Repeated Ca(2+) sparks from individual sites were analysed in the presence of 50 nM ryanodine with: (i) no additional agents (control); (ii) 50 µM caffeine to sensitize RyRs; (iii) 50 µM tetracaine to inhibit RyRs; or (iv) 100 nM isoproterenol to activate β-adrenergic receptors. Sensitization and inhibition of RyR clusters shortened and lengthened, respectively, the median interval between consecutive Ca(2+) sparks (caffeine 239 ms; control 280 ms; tetracaine 453 ms). Recovery of Ca(2+) spark amplitude, however, was exponential with a time constant of ∼100 ms in all cases. Isoproterenol both accelerated the recovery of Ca(2+) spark amplitude (τ = 58 ms) and shortened the median interval between Ca(2+) sparks (192 ms). The results were recapitulated by a mathematical model in which SR [Ca(2+)] depletion terminates Ca(2+) sparks, but not by an alternative model based on limited depletion and Ca(2+)-dependent inactivation of RyRs.
  
  
  CONCLUSIONS
  Together, the results strongly suggest that: (i) local SR refilling controls Ca(2+) spark amplitude recovery; (ii) Ca(2+) spark triggering depends on both refilling and RyR sensitivity; and (iii) β-adrenergic stimulation influences both processes.
authors: Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, One Gustave Levy Place, Box 1215, New York, NY 10029, USA.
authors: Hena R
authors: HR
authors: Ramay
authors: Ona Z
authors: OZ
authors: Liu
authors: Eric A
authors: EA
authors: Sobie
references: Circ Res. 2005 May 27;96(10):e77-82
references: 15890976
references: J Cardiovasc Electrophysiol. 2006 May;17 Suppl 1:S64-S70
references: 16686684
references: Circ Res. 2007 Feb 16;100(3):391-8
references: 17234966
references: Circ Res. 2010 May 28;106(10):1582-91
references: 20378857
references: Science. 1993 Oct 29;262(5134):740-4
references: 8235594
references: Biophys J. 2008 Oct;95(8):3767-89
references: 18676655
references: J Gen Physiol. 2008 Apr;131(4):325-34
references: 18347081
references: Biophys J. 2010 Jun 2;98(11):2515-23
references: 20513395
references: Biophys J. 2002 Jul;83(1):59-78
references: 12080100
references: Circ Res. 2002 Sep 6;91(5):414-20
references: 12215490
references: Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):18028-33
references: 19815510
references: Am J Physiol Cell Physiol. 2001 May;280(5):C1327-39
references: 11287346
references: J Biol Chem. 1991 Jun 15;266(17):11144-52
references: 1645727
references: Biophys J. 2007 May 15;92(10):3541-55
references: 17351009
references: J Clin Invest. 2006 Sep;116(9):2510-20
references: 16932808
references: Circ Res. 2004 Oct 15;95(8):807-13
references: 15388639
references: Biophys J. 2001 Aug;81(2):785-98
references: 11463625
references: Biophys J. 2004 Apr;86(4):2121-8
references: 15041652
references: J Physiol. 2010 Jan 1;588(Pt 1):225-42
references: 19900959
references: Heart Rhythm. 2009 Jan;6(1):123-9
references: 19121813
references: Trends Cardiovasc Med. 2004 Feb;14(2):61-6
references: 15030791
references: J Physiol. 2005 Jun 1;565(Pt 2):441-7
references: 15817631
references: J Cardiovasc Electrophysiol. 2009 Oct;20(10):1179-85
references: 19563351
references: Biophys J. 1998 Jul;75(1):15-32
references: 9649364
references: Nat Cell Biol. 1999 Oct;1(6):323-9
references: 10559957
references: Circ Res. 2008 Oct 10;103(8):e105-15
references: 18787194
references: Biophys J. 2008 Mar 1;94(5):1867-79
references: 18024505
references: J Gen Physiol. 2008 Apr;131(4):335-48
references: 18347079
references: Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):3099-104
references: 15710901
references: Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11759-64
references: 13130076
references: J Physiol. 2009 Oct 15;587(Pt 20):4863-72
references: 19703963
references: Biophys J. 2009 Apr 8;96(7):2744-54
references: 19348757
references: Nature. 2002 Jan 10;415(6868):198-205
references: 11805843
references: Circ Res. 2003 Jul 11;93(1):40-5
references: 12791706
references: Circ Res. 2002 Feb 22;90(3):309-16
references: 11861420
references: Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2982-7
references: 16473932
references: J Physiol. 1996 Oct 15;496 ( Pt 2):575-81
references: 8910239
references: Cardiovasc Res. 2008 Jan 15;77(2):293-301
references: 18006488