β-adrenergic stimulation synchronizes intracellular Ca2+ release during excitation-contraction coupling in cardiac myocytes

Long Sheng Song, Shi Qiang Wang, Rui Ping Xiao, Harold Spurgeon, Edward G. Lakatta, Heping Cheng

Research output: Contribution to journalArticlepeer-review

Abstract

To elucidate microscopic mechanisms underlying the modulation of cardiac excitation-contraction (EC) coupling by β-adrenergic receptor (β-AR) stimulation, we examined local Ca2+ release function, ie, Ca2+ spikes at individual transverse tubule-sarcoplasmic reticulum (T-SR) junctions, using confocal microscopy and our recently developed technique for release flux measurement. β-AR stimulation by norepinephrine plus an α1-adrenergic blocker, prazosin, increased the amplitude of SR Ca2+ release flux (JSR), its running integral (∫JSR), and L-type Ca2+ channel current (ICa, and it shifted their bell-shaped voltage dependence leftward by ≈ 10 mV, with the relative effects ranking ICa> JSR>∫JSR. Confocal imaging revealed that the bell-shaped voltage dependence of SR Ca2+ release is attributable to a graded recruitment of T-SR junctions as well as to changes in Ca2+ spike amplitudes. β-AR stimulation increased the fractional T-SR junctions that fired Ca2+ spikes and augmented Ca2+ spike amplitudes, without altering the SR Ca2+ load, suggesting that more release units were activated synchronously among and within T-SR junctions. Moreover, β-AR stimulation decreased the latency and temporal dispersion of Ca2+ spike occurrence at a given voltage, delivering most of the Ca2+ at the onset of depolarization rather than spreading it out throughout depolarization. Because the synchrony of Ca2+ spikes affects Ca2+ delivery per unit of time to contractile myofilaments, and because the: myofilaments display a steep Ca2+ dependence, our data suggest that synchronization of SR Ca2+ release represents a heretofore unappreciated mechanism of β-AR modulation of cardiac inotropy.

Original languageEnglish (US)
Pages (from-to)794-801
Number of pages8
JournalCirculation research
Volume88
Issue number8
DOIs
StatePublished - Apr 27 2001
Externally publishedYes

Keywords

  • Excitation-contraction coupling
  • Heart cells
  • Ryanodine receptors
  • β-adrenergic receptor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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