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Updated: May 31, 2026

Functional Characterization of Endogenously Expressed Human RYR1 Variants
Published on: June 9, 2021
Pathogenic CaV1.1 Variants Cause Hyperpolarizing Shift of Depolarization-Induced Ca2+ Release in Malignant
Takashi Murayama1, Takuro Numaga-Tomita2, Hirotsugu Miyoshi3
1Department of Pharmacology, Juntendo University School of Medicine, Tokyo, Japan. takashim@juntendo.ac.jp.
Abstract:
Malignant hyperthermia (MH) is a potentially fatal genetic disorder triggered by certain anesthetics, leading to excessive calcium release in skeletal muscle. While most MH-associated mutations affect the type 1 ryanodine receptor, a Ca2+ release channel in the sarcoplasmic reticulum, variants in CaV1.1-the L-type calcium channel critical for excitation-contraction coupling-have also been implicated. Here, we investigate four novel CaV1.1 variants identified in MH-susceptible individuals (A560T, S879P, F1161L, and D1382V) using a reconstituted Ca2+ release platform in HEK293 cells. Two variants, S879P and F1161L, increase sensitivity to extracellular potassium of depolarization-induced Ca2+ release (DICR), enhance caffeine responsiveness, and shift voltage sensing toward more hyperpolarized potential. Interestingly, enhanced caffeine sensitivity is abolished by loss of DICR at rest. These findings suggest that hyperpolarizing shift of DICR underlies Ca2+ dysregulation in S879P and F1161L CaV1.1-linked MH. Our findings uncover a mechanistic link between CaV1.1 variants and MH susceptibility, highlighting the pathological role of DICR.
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