Effects of MH and CCD Mutations in the Central Region on RyR1 Channels

Abstract

Type 1 ryanodine receptor (RyR1) is a Ca2+ release channel in the sarcoplasmic reticulum and the major target for muscle diseases, e.g., malignant hyperthermia (MH) and central core disease (CCD). It is widely believed that MH and CCD mutations cause hyperactivation of the Ca2+-induced Ca2+ release (CICR), resulting in abnormal Ca2+ homeostasis in skeletal muscle. However, it remains unclear how the disease-associated mutations affect CICR. We have recently characterized several disease-associated mutations in the amino-terminal region by live-cell Ca2+ imaging and [3H]ryanodine binding and found that these mutations divergently affect the gain (i.e., peak activity) and the sensitivity to activating Ca2+ of CICR. In this study, we extended this approach to 15 MH and MH/CCD mutations in the central region (1592-2508). The disease-associated mutations increased the gain and the sensitivity to activating Ca2+ in a site-dependent manner. The calculated CICR activity strongly correlated with the ER Ca2+ level, an index of Ca2+ leak. Importantly, the accelerated sensitivity to activating Ca2+ was linked to pathogenesis of CCD. Overall, the effects were similar to those of the amino-terminal mutations. The underlying molecular mechanism will be discussed.