PURPOSE Malignant hyperthermia (MH) is a pharmacogenetic disorder arising from uncontrolled muscle calcium release due to an abnormality in the sarcoplasmic reticulum (SR) calcium-release mechanism triggered by halogenated inhalational anesthetics. However, the molecular mechanisms involved are still incomplete. METHODS We aimed to identify transient receptor potential vanilloid 1 (TRPV1) variants within the entire coding sequence in patients who developed sensitivity to MH of unknown etiology. In vitro and in vivo functional studies were performed in heterologous expression system, trpv1-/- mice, and a murine model of human MH. RESULTS We identified TRPV1 variants in two patients and their heterologous expression in muscles of trpv1-/- mice strongly enhanced calcium release from SR upon halogenated anesthetic stimulation, suggesting they could be responsible for the MH phenotype. We confirmed the in vivo significance by using mice with a knock-in mutation (Y524S) in the type I ryanodine receptor (Ryr1), a mutation analogous to the Y522S mutation associated with MH in humans. We showed that the TRPV1 antagonist capsazepine slows the heat-induced hypermetabolic response in this model. CONCLUSION We propose that TRPV1 contributes to MH and could represent an actionable therapeutic target for prevention of the pathology and also be responsible for MH sensitivity when mutated.

中文翻译：

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TRPV1 变体损害细胞内 Ca2+ 信号传导，并可能导致对恶性高热的易感性。

目的 恶性高热 (MH) 是一种药物遗传学疾病，由卤化吸入麻醉剂引发的肌浆网 (SR) 钙释放机制异常引起的肌肉钙释放失控引起。然而，所涉及的分子机制仍然不完整。方法 我们的目的是在对病因不明的 MH 敏感的患者的整个编码序列中识别瞬时受体电位 vanilloid 1 (TRPV1) 变体。在异源表达系统、trpv1-/- 小鼠和人类 MH 小鼠模型中进行了体外和体内功能研究。结果 我们在两名患者中发现了 TRPV1 变异体，它们在 trpv1-/- 小鼠肌肉中的异源表达强烈增强了卤化麻醉刺激后 SR 中钙的释放，表明他们可能对 MH 表型负责。我们通过使用在 I 型兰尼碱受体 (Ryr1) 中具有敲入突变 (Y524S) 的小鼠证实了体内意义，该突变类似于与人类 MH 相关的 Y522S 突变。我们发现 TRPV1 拮抗剂 capsazepine 在该模型中减缓了热诱导的高代谢反应。结论 我们提出 TRPV1 对 MH 有贡献，并且可以代表预防病理学的可行治疗靶点，并且在突变时也对 MH 敏感性负责。我们发现 TRPV1 拮抗剂 capsazepine 在该模型中减缓了热诱导的高代谢反应。结论 我们提出 TRPV1 对 MH 有贡献，并且可以代表预防病理学的可行治疗靶点，并且在突变时也对 MH 敏感性负责。我们发现 TRPV1 拮抗剂 capsazepine 在该模型中减缓了热诱导的高代谢反应。结论 我们提出 TRPV1 对 MH 有贡献，并且可以代表预防病理学的可行治疗靶点，并且在突变时也对 MH 敏感性负责。