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(Circulation Research. 2007;101:590.)
© 2007 American Heart Association, Inc.

Cellular Biology

Voltage Dependence of Cardiac Excitation–Contraction Coupling

Unitary Ca²⁺ Current Amplitude and Open Channel Probability

Julio Altamirano, Donald M. Bers

From the Department of Physiology, Loyola University Chicago, Maywood, Ill. Present address for J.A.: Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore.

Correspondence to Donald M. Bers, PhD, Department of Physiology, Loyola University Chicago, Stritch School of Medicine, 2160 S First Ave, Maywood, IL 60153. E-mail dbers{at}lumc.edu

Excitation–contraction coupling in cardiac myocytes occurs by Ca²⁺-induced Ca²⁺ release, where L-type Ca²⁺ current evokes a larger sarcoplasmic reticulum (SR) Ca²⁺ release. The Ca²⁺-induced Ca²⁺ release amplification factor or gain (SR Ca²⁺ release/I_Ca) is usually assessed by the V_m dependence of current and Ca²⁺ transients. Gain rises at negative V_m, as does single channel I_Ca (i_Ca), which has led to the suggestion that the increases of i_Ca amplitude enhances gain at more negative V_m. However, I_Ca=NP_oxi_Ca (where NP_o is the number of open channels), and NP_o and i_Ca both depend on V_m. To assess how i_Ca and NP_o separately influence Ca²⁺-induced Ca²⁺ release, we measured I_Ca and junctional SR Ca²⁺ release in voltage-clamped rat ventricular myocytes using "Ca²⁺ spikes" (confocal microscopy). To vary i_Ca alone, we changed [Ca²⁺]_o rapidly at constant test V_m (0 mV) or abruptly repolarized from +120 mV to different V_m (at constant [Ca²⁺]_o). To vary NP_o alone, we altered Ca²⁺ channel availability by varying holding V_m (at constant test V_m). Reducing either i_Ca or NP_o alone increased excitation–contraction coupling gain. Thus, increasing i_Ca does not increase gain at progressively negative test V_m. Such enhanced gain depends on lower NP_o and reduced redundant Ca²⁺ channel openings (per junction) and a consequently smaller denominator in the gain equation. Furthermore, modest i_Ca (at V_m=0 mV) may still effectively trigger SR Ca²⁺ release, whereas at positive V_m (and smaller i_Ca), high and well-synchronized channel openings are required for efficient excitation–contraction coupling. At very positive V_m, reduced i_Ca must explain reduced SR Ca²⁺ release.

Key Words: calcium-induced calcium release • excitation–contraction coupling

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