Regulation of dynamic behavior of cardiac ryanodine receptor by Mg2+ under simulated physiological conditions.

, , , , , and . Am. J. Physiol. Cell Physiol. 285 (5): C1059--C1070 (November 2003)


Mg2+, an important constituent of the intracellular milieu in cardiac myocytes, is known to inhibit ryanodine receptor (RyR) Ca$^2+$ release channels by competing with Ca$^2+$ at the cytosolic activation sites of the channel. However, the significance of this competition for local, dynamic Ca$^2+$-signaling processes thought to govern cardiac excitation-contraction (EC) coupling remains largely unknown. In the present study, Ca$^2+$ stimuli of different waveforms (i.e., sustained and brief) were generated by photolysis of the caged Ca$^2+$ compound nitrophenyl (NP)-EGTA. The evoked RyR activity was measured in planar lipid bilayers in the presence of 0.6-1.3 mM free Mg2+ at the background of 3 mM total ATP in the presence or absence of 1 mM luminal Ca$^2+$. Mg2+ dramatically slowed the rate of activation of RyRs in response to sustained (> or =10-ms) elevations in Ca$^2+$ concentration. Paradoxically, Mg2+ had no measurable impact on the kinetics of the RyR response induced by physiologically relevant, brief (<1-ms) Ca$^2+$ stimuli. Instead, the changes in activation rate observed with sustained stimuli were translated into a drastic reduction in the probability of responses. Luminal Ca$^2+$ did not affect the peak open probability or the probability of responses to brief Ca$^2+$ signals; however, it slowed the transition to steady state and increased the steady-state open probability of the channel. Our results indicate that Mg2+ is a critical physiological determinant of the dynamic behavior of the RyR channel, which is expected to profoundly influence the fidelity of coupling between L-type Ca$^2+$ channels and RyRs in heart cells.


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