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1 Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Bratislava, Slovakia (Slovak Republic)
2 Department of Physiology, Texas Tech University Health Sciences Center, Lubbock, TX, USA
* To whom correspondence should be addressed. E-mail: alexandra.zahradnikova{at}savba.sk.
The magnesium ion, an important constituent of the intracellular milieu in cardiac myocytes, is known to inhibit ryanodine receptor (RyR) Ca2+ release channels by competing with Ca2+ at the cytosolic activation sites of the channel. However, the significance of this competition for local, dynamic Ca2+ signaling processes thought to govern cardiac excitation-contraction (EC) coupling remains largely unknown. In the present study, calcium stimuli of different waveforms (i.e., sustained and brief) were generated by photolysis of the caged Ca2+ compound 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 Ca2+. Mg2+ dramatically slowed the rate of activation of RyRs in response to sustained [Ca2+] elevations (
10 ms). Paradoxically, Mg2+ had no measurable impact on the kinetics of the RyR response induced by physiologically relevant, brief (< 1ms) Ca2+ stimuli. Instead, the changes in activation rate observed with sustained stimuli were translated into a drastic reduction in the probability of responses. Luminal Ca2+ did not affect the peak open probability or the probability of responses to brief Ca2+ signals; however, it slowed the transition into 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 Ca2+ channels and RyRs in heart cells.
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