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A Retrograde Signal from RyR1 Alters DHP Receptor Inactivation and Limits Window Ca²⁺ Release in Muscle Fibers of Y522S RyR1 Knock-In Mice

Zoita Andronache, Susan L. Hamilton, Robert T. Dirksen, Werner Melzer and David Julius
Proceedings of the National Academy of Sciences of the United States of America
Vol. 106, No. 11 (Mar. 17, 2009), pp. 4531-4536
Stable URL: http://www.jstor.org/stable/40441843
Page Count: 6
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
A Retrograde Signal from RyR1 Alters DHP Receptor
                            Inactivation and Limits Window Ca²⁺ Release in Muscle Fibers of Y522S
                            RyR1 Knock-In Mice
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Abstract

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 $RYR1^{Y522S} $-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 $RYR1^{Y522S} $-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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