Interdomain interaction within type 1 ryanodine receptor is involved in dysfunction of Ca²⁺ release channel in malignant hyperthermia

Abstract

Malignant hyperthermia (MH) is an inherited disorder caused by a missense mutation of type 1 ryanodine receptor (RyR1) of skeletal muscle. We have recently showed that Ca²⁺-induced Ca²⁺ release (CICR) activity of RyR1 in the SR is selectively stabilized by a probable interdomain interaction between the N-terminal and the central regions of RyR1 where many of mutated sites for MH are clustered (Murayama et al., Am. J. Physiol. 288; C1222-C1230, 2005). According to our hypothesis, a mutation within these regions will weaken the interdomain interaction, resulting in an increased CICR activity. We are presenting here further evidence to support this hypothesis using SR vesicles from skeletal muscles of wild type and MH pigs carrying the N-terminal Arg615Cys mutation in RyR1. Furthermore, we will show results using RyR1 channels carrying several human MH mutations including those in the C-terminal region that are stably expressed in HEK293 cells. [J Physiol Sci. 2006;56 Suppl:S156]