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<p>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 Ca<sup>2+</sup> release channel in the sarcoplasmic reticulum, variants in Ca<sub>V</sub>1.1—the L-type calcium channel critical for excitation–contraction coupling—have also been implicated. Here, we investigate four novel Ca<sub>V</sub>1.1 variants identified in MH-susceptible individuals (A560T, S879P, F1161L, and D1382V) using a reconstituted Ca<sup>2+</sup> release platform in HEK293 cells. Two variants, S879P and F1161L, increase sensitivity to extracellular potassium of depolarization-induced Ca<sup>2+</sup> 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 Ca<sup>2+</sup> dysregulation in S879P and F1161L Ca<sub>V</sub>1.1-linked MH. Our findings uncover a mechanistic link between Ca<sub>V</sub>1.1 variants and MH susceptibility, highlighting the pathological role of DICR.</p>

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Pathogenic CaV1.1 Variants Cause Hyperpolarizing Shift of Depolarization-Induced Ca2+ Release in Malignant Hyperthermia Susceptibility

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月29日

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  • Takashi Murayama,
  • Takuro Numaga-Tomita,
  • Hirotsugu Miyoshi,
  • Tsuyoshi Ikeda,
  • Keiko Mukaida,
  • Takuya Kobayashi,
  • Nagomi Kurebayashi,
  • Tsutomu Nakada,
  • Taichiro Tomida,
  • Satomi Adachi-Akahane,
  • Yasuo M. Tsutsumi,
  • Mitsuhiko Yamada,
  • Takashi Sakurai

摘要

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.