Affected interdomain interactions within type 1 ryanodine receptor underlie its dysfunction in malignant hyperthermia

Abstract

We have recently demonstrated that type 1 ryanodine receptor (RyR1) exhibits lower gain of Ca²⁺-induced Ca²⁺ release (CICR) activity than type 3 (RyR3) in mammalian skeletal muscle sarcoplasmic reticulum (SR). The lowered gain was reversed by CHAPS and DP4, a peptide corresponding to the Leu²⁴⁴²-Pro²⁴⁷⁷ region of rabbit RyR1, indicating hypothesized interactions between the N-terminal and the central domains of RyR might underlie channel dysfunction in malignant hyperthermia (MH) which shows mutations within these domains. In this study, we tested this hypothesis by comparing [³H]ryanodine binding to the SR vesicles from wild-type (WT) and MH-susceptible (MHS) pigs carrying RyR1 Arg⁶¹⁵Cys mutation. Caffeine-induced Ca²⁺ release was more enhanced with the SR from MHS as compared to those from WT. RyR1_MHS exhibited gain 8-fold greater than RyR1_WT with minor change in sensitivity to endogenous ligands including Ca²⁺, Mg²⁺, and ATP. Thus, the enhanced activity of RyR1_MHS is primarily due to a greater gain of the mutated channel. DP4 markedly activated RyR1_WT, whereas little activation with RyR1_MHS. These findings support the notion that increase in the gain of RyR1 by weakened interdomain interactions underlies MH. [Jpn J Physiol 55 Suppl:S137 (2005)]