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Distinct Effects on Ca²⁺ Handling Caused by Malignant Hyperthermia and Central Core Disease Mutations in RyR1

Robert T. Dirksen ^* and Guillermo Avila 

^* Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York USA; and Centro de Investigaciones y de Estudios Avanzados del IPN, Mexico City, Mexico

Correspondence: Address reprint requests to Guillermo Avila, Dept. of Biochemistry, Cinvestav-IPN AP 14-740, Mexico City, DF 07000, Mexico. Tel.: 52-55-5061-3952; Fax: 52-55-5747-7083; E-mail: gavila{at}mail.cinvestav.mx.

Malignant hyperthermia (MH) and central core disease (CCD) are disorders of skeletal muscle Ca²⁺ homeostasis that are linked to mutations in the type 1 ryanodine receptor (RyR1). Certain RyR1 mutations result in an MH-selective phenotype (MH-only), whereas others result in a mixed phenotype (MH + CCD). We characterized effects on Ca²⁺ handling and excitation-contraction (EC) coupling of MH-only and MH + CCD mutations in RyR1 after expression in skeletal myotubes derived from RyR1-null (dyspedic) mice. Compared to wild-type RyR1-expressing myotubes, MH + CCD- and MH-only-expressing myotubes exhibited voltage-gated Ca²⁺ release (VGCR) that activated at more negative potentials and displayed a significantly higher incidence of spontaneous Ca²⁺ oscillations. However, maximal VGCR was reduced only for MH + CCD mutants (Y4795C, R2435L, and R2163H) in which spontaneous Ca²⁺ oscillations occurred with significantly longer duration (Y4795C and R2435L) or higher frequency (R2163H). Notably, myotubes expressing these MH + CCD mutations in RyR1 exhibited both increased [Ca²⁺]_i and reduced sarcoplasmic reticulum (SR) Ca²⁺ content. We conclude that MH-only mutations modestly increase basal release-channel activity in a manner insufficient to alter net SR Ca²⁺ content ("compensated leak"), whereas the mixed MH + CCD phenotype arises from mutations that enhance basal activity to a level sufficient to promote SR Ca²⁺ depletion, elevate [Ca²⁺]_i, and reduce maximal VGCR ("decompensated leak").

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