$\beta$-Adrenergic stimulation synchronizes intracellular Ca$^2+$ release during excitation-contraction coupling in cardiac myocytes.

, , , , , and . Circ. Res. 88 (8): 794--801 (April 2001)


To elucidate microscopic mechanisms underlying the modulation of cardiac excitation-contraction (EC) coupling by beta-adrenergic receptor (beta-AR) stimulation, we examined local Ca$^2+$ release function, ie, Ca$^2+$ spikes at individual transverse tubule-sarcoplasmic reticulum (T-SR) junctions, using confocal microscopy and our recently developed technique for release flux measurement. beta-AR stimulation by norepinephrine plus an alpha(1)-adrenergic blocker, prazosin, increased the amplitude of SR Ca$^2+$ release flux (J(SR)), its running integral (integralJ(SR)), and L-type Ca$^2+$ channel current (I(Ca)), and it shifted their bell-shaped voltage dependence leftward by approximately 10 mV, with the relative effects ranking I(Ca)> J(SR)>integralJ(SR). Confocal imaging revealed that the bell-shaped voltage dependence of SR Ca$^2+$ release is attributable to a graded recruitment of T-SR junctions as well as to changes in Ca$^2+$ spike amplitudes. beta-AR stimulation increased the fractional T-SR junctions that fired Ca$^2+$ spikes and augmented Ca$^2+$ spike amplitudes, without altering the SR Ca$^2+$ load, suggesting that more release units were activated synchronously among and within T-SR junctions. Moreover, beta-AR stimulation decreased the latency and temporal dispersion of Ca$^2+$ spike occurrence at a given voltage, delivering most of the Ca$^2+$ at the onset of depolarization rather than spreading it out throughout depolarization. Because the synchrony of Ca$^2+$ spikes affects Ca$^2+$ delivery per unit of time to contractile myofilaments, and because the myofilaments display a steep Ca$^2+$ dependence, our data suggest that synchronization of SR Ca$^2+$ release represents a heretofore unappreciated mechanism of beta-AR modulation of cardiac inotropy.


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