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• W4383671868 abstract "Cardiac excitation-contraction coupling (ECC) depends on Ca2+ release from intracellular stores via ryanodine receptors (RyRs) triggered by L-type Ca2+ channels (LCCs). Uncertain numbers of RyRs and LCCs form 'couplons' whose activation produces Ca2+ sparks, which summate to form a cell-wide Ca2+ transient that switches on contraction. Voltage (Vm) changes during the action potential (AP) and stochasticity in channel gating should create variability in Ca2+ spark timing, but Ca2+ transient wavefronts have remarkable uniformity. To examine how this is achieved, we measured the Vm-dependence of evoked Ca2+ spark probability (Pspark) and latency over a wide voltage range in rat ventricular cells. With depolarising steps, Ca2+ spark latency showed a U-shaped Vm-dependence, while repolarising steps from 50 mV produced Ca2+ spark latencies that increased monotonically with Vm. A computer model based on reported channel gating and geometry reproduced our experimental data and revealed a likely RyR:LCC stoichiometry of ∼ 5:1 for the Ca2+ spark initiating complex (IC). Using the experimental AP waveform, the model revealed a high coupling fidelity (Pcpl ∼ 0.5) between each LCC opening and IC activation. The presence of ∼ 4 ICs per couplon reduced Ca2+ spark latency and increased Pspark to match experimental data. Variability in AP release timing is less than that seen with voltage steps because the AP overshoot and later repolarization decrease Pspark due to effects on LCC flux and LCC deactivation respectively. This work provides a framework for explaining the Vm- and time-dependence of Pspark, and indicates how ion channel dispersion in disease can contribute to dyssynchrony in Ca2+ release." @default.
• W4383671868 created "2023-07-09" @default.
• W4383671868 creator A5043195980 @default.
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• W4383671868 date "2023-09-01" @default.
• W4383671868 modified "2023-09-26" @default.
• W4383671868 title "Ca2+ spark latency and control of intrinsic Ca2+ release dyssynchrony in rat cardiac ventricular muscle cells" @default.
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• W4383671868 doi "https://doi.org/10.1016/j.yjmcc.2023.07.005" @default.
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• W4383671868 hasPublicationYear "2023" @default.
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