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Circulation Research. 2001;88:794-801
Published online before print April 13, 2001, doi: 10.1161/hh0801.090461
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(Circulation Research. 2001;88:794.)
© 2001 American Heart Association, Inc.

Cellular Biology

ß-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

From the Laboratory of Cardiovascular Sciences (L.-S.S., S.-Q.W., R.-P.X., H.S., E.G.L., H.C.), National Institute on Aging, National Institutes of Health, Baltimore, Md; and National Laboratory of Biomembrane and Membrane Biotechnology (H.C.), College of Life Sciences, Peking University, Beijing, China.

Correspondence to Heping Cheng, PhD, Laboratory of Cardiovascular Sciences, National Institute on Aging, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail chengp{at}grc.nia.nih.gov

Abstract—To elucidate microscopic mechanisms underlying the modulation of cardiac excitation-contraction (EC) coupling by ß-adrenergic receptor (ß-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. ß-AR stimulation by norepinephrine plus an {alpha}1-adrenergic blocker, prazosin, increased the amplitude of SR Ca2+ release flux (JSR), its running integral ({int}JSR), and L-type Ca2+ channel current (ICa), and it shifted their bell-shaped voltage dependence leftward by {approx}10 mV, with the relative effects ranking ICa> JSR>{int}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. ß-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, ß-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 ß-AR modulation of cardiac inotropy.


Key Words: excitation-contraction coupling • ß-adrenergic receptor • L-type Ca2+ channel current • ryanodine receptors • heart cells




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