Calmodulin sensitivity of the sarcoplasmic reticulum ryanodine receptor from normal and malignant-hyperthermia-susceptible muscle Available to Purchase

Ca²⁺ release from sarcoplasmic reticulum (SR) of malignant-hyperthermia-susceptible (MHS) muscle is hypersensitive to Ca²⁺ and caffeine. To determine if an abnormal calmodulin (CaM) regulation of the SR Ca²⁺-release-channel-ryanodine-receptor complex (RYR1) contributes to this hypersensitivity, we investigated the effect of CaM on high-affinity [³H]ryanodine binding to isolated SR vesicles from normal and MHS pig skeletal muscle. CaM modulated [³H]ryanodine binding in a Ca²⁺-dependent manner. In the presence of maximally activating Ca²⁺ concentrations, CaM inhibited [³H]ryanodine binding with no differences between normal and MHS vesicles. In the absence of Ca²⁺, however, CaM activated [³H]ryanodine binding with a 2-fold-higher potency in MHS vesicles. Significant differences between normal and MHS tissue were observed for CaM concentrations between 50 nM and 10 µM. A polyclonal antibody raised against the central region of RYR1 specifically inhibited this activating effect of CaM without affecting the inhibition by CaM. This indicates that the central region of RYR1 is a potential binding domain for CaM in the absence of Ca²⁺. It is suggested that in vivo an enhanced CaM sensitivity of RYR1 might contribute to the abnormal high release of Ca²⁺ from the SR of MHS muscle.