Malignant hyperthermia-associated mutations in the S2-S3 cytoplasmic loop of type 1 ryanodine receptor calcium channel impair calcium-dependent inactivation

Author:

Gomez Angela C.12,Holford Timothy W.12,Yamaguchi Naohiro12

Affiliation:

1. Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina; and

2. Cardiac Signaling Center of University of South Carolina, Medical University of South Carolina, and Clemson University, Charleston, South Carolina

Abstract

Channel activities of skeletal muscle ryanodine receptor (RyR1) are activated by micromolar Ca2+ and inactivated by higher (∼1 mM) Ca2+. To gain insight into a mechanism underlying Ca2+-dependent inactivation of RyR1 and its relationship with skeletal muscle diseases, we constructed nine recombinant RyR1 mutants carrying malignant hyperthermia or centronuclear myopathy-associated mutations and determined RyR1 channel activities by [3H]ryanodine binding assay. These mutations are localized in or near the RyR1 domains which are responsible for Ca2+-dependent inactivation of RyR1. Four RyR1 mutations (F4732D, G4733E, R4736W, and R4736Q) in the cytoplasmic loop between the S2 and S3 transmembrane segments (S2–S3 loop) greatly reduced Ca2+-dependent channel inactivation. Activities of these mutant channels were suppressed at 10–100 μM Ca2+, and the suppressions were relieved by 1 mM Mg2+. The Ca2+- and Mg2+-dependent regulation of S2–S3 loop RyR1 mutants are similar to those of the cardiac isoform of RyR (RyR2) rather than wild-type RyR1. Two mutations (T4825I and H4832Y) in the S4–S5 cytoplasmic loop increased Ca2+ affinities for channel activation and decreased Ca2+ affinities for inactivation, but impairment of Ca2+-dependent inactivation was not as prominent as those of S2–S3 loop mutants. Three mutations (T4082M, S4113L, and N4120Y) in the EF-hand domain showed essentially the same Ca2+-dependent channel regulation as that of wild-type RyR1. The results suggest that nine RyR1 mutants associated with skeletal muscle diseases were differently regulated by Ca2+ and Mg2+. Four malignant hyperthermia-associated RyR1 mutations in the S2–S3 loop conferred RyR2-type Ca2+- and Mg2+-dependent channel regulation.

Publisher

American Physiological Society

Subject

Cell Biology,Physiology

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