Malignant hyperthermia (MH) is a life-threatening hypermetabolic condition caused by dysfunctional Ca2+ homeostasis in skeletal muscle, which primarily originates from genetic alterations in the Ca2+ release channel (ryanodine receptor, RyR1) of the sarcoplasmic reticulum (SR). Owing to its physical interaction with the dihydropyridine receptor (DHPR), RyR1 is controlled by the electrical potential across the transverse tubular (TT) membrane. The DHPR exhibits both voltage-dependent activation and inactivation. Here we determined the impact of an MH mutation in RyR1 (Y522S) on these processes in adult muscle fibers isolated from heterozygous RyR1Y522S-knock-in mice. The voltage dependence of DHPR-triggered Ca2+ release flux was left-shifted by ≈8 mV. As a consequence, the voltage window for steady-state Ca2+ release extended to more negative holding potentials in muscle fibers of the RyR1Y522S-mice. A rise in temperature from 20° to 30 °C caused a further shift to more negative potentials of this window (by ≈20 mV). The activation of the DHPR-mediated Ca2+ current was minimally changed by the mutation. However, surprisingly, the voltage dependence of steady-state inactivation of DHPR-mediated calcium conductance and release were also shifted by ≈10 mV to more negative potentials, indicating a retrograde action of the RyR1 mutation on DHPR inactivation that limits window Ca2+ release. This effect serves as a compensatory response to the lowered voltage threshold for Ca2+ release caused by the Y522S mutation and represents a novel mechanism to counteract excessive Ca2+ leak and store depletion in MH-susceptible muscle
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