Pathogenic Ca1.1 Variants Cause Hyperpolarizing Shift of Depolarization-Induced CaRelease in Malignant Hyperthermia Susceptibility.

Source: PubMed, NCBI / U.S. National Library of Medicine

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 Carelease channel in the sarcoplasmic reticulum, variants in Ca1.1-the L-type calcium channel critical for excitation-contraction coupling-have also been implicated. Here, we investigate four novel Ca1.1 variants identified in MH-susceptible individuals (A560T, S879P, F1161L, and D1382V) using a reconstituted Carelease platform in HEK293 cells. Two variants, S879P and F1161L, increase sensitivity to extracellular potassium of depolarization-induced Carelease (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 Cadysregulation in S879P and F1161L Ca1.1-linked MH. Our findings uncover a mechanistic link between Ca1.1 variants and MH susceptibility, highlighting the pathological role of DICR.