Impaired interaction between skeletal ryanodine receptors in malignant hyperthermia.

Functional coupling between clustered membrane receptors has been identified as a novel mechanism to improve signaling performance in a number of physiological processes. The potential role of defective inter-receptor coupling in the pathogenesis of disease, however, has not previously been explored. Ryanodine receptors (RyRs), the primary calcium release channel of muscle, usually form ordered two-dimensional arrays in the sarcoplasmic reticulum membranes. Mutations in RyRs are known to cause a number of severe diseases both in skeletal muscle and in heart. Here we present a model demonstrating how impaired functional coupling between neighboring mutant RyR1(R615C) channels may contribute to the pharmacogenetic skeletal muscle sensitivity, malignant hyperthermia (MH). We find that purified RyR1(R615C) from MH susceptible porcine skeletal muscle shows significantly reduced oligomerization when compared to RyR1(WT), indicating a potential loss of intrinsic intermolecular control. The MH-triggering volatile anesthetic, halothane, activates RyR1(R615C) and RyR1(WT) to a similar extent, using [(3)H]ryanodine binding as a measure of activation. Modeling RyR1 array function with parameters modified to simulate the loss of functional inter-RyR coupling recapitulates the MH molecular phenotype-RyR1 channels leaky to Ca(2+) at rest and long open-times following exposure to halothane. Our work suggests that a defect in inter-RyR1 coupling is a novel direction for research into the pathogenesis of MH.