期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：32
DOI：10.1073/pnas.2201286119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Malignant hyperthermia (MH) is a life-threatening disorder caused largely by mutations in ryanodine receptor type 1 (RyR1) Ca
2+-release channels. Enhanced Ca
2+ release through the mutant channels induces excessive heat development upon exposure to volatile anesthetics. However, the mechanism by which Ca
2+ release is accelerated at an elevated temperature is yet to be identified. Fluorescence Ca
2+ imaging with rapid heating by an infrared laser beam provides direct evidence that heat induces Ca
2+ release through the RyR1 channel. And the mutant channels are more heat sensitive than the wild-type channels, thereby causing an increase in the cytosolic Ca
2+ concentration in mutant cells. It is likely that the heat-induced Ca
2+ release participates as an enhancer in the cellular mechanism of MH.
Thermoregulation is an important aspect of human homeostasis, and high temperatures pose serious stresses for the body. Malignant hyperthermia (MH) is a life-threatening disorder in which body temperature can rise to a lethal level. Here we employ an optically controlled local heat-pulse method to manipulate the temperature in cells with a precision of less than 1 °C and find that the mutants of ryanodine receptor type 1 (RyR1), a key Ca
2+ release channel underlying MH, are heat hypersensitive compared with the wild type (WT). We show that the local heat pulses induce an intracellular Ca
2+ burst in human embryonic kidney 293 cells overexpressing WT RyR1 and some RyR1 mutants related to MH. Fluorescence Ca
2+ imaging using the endoplasmic reticulum–targeted fluorescent probes demonstrates that the Ca
2+ burst originates from heat-induced Ca
2+ release (HICR) through RyR1-mutant channels because of the channels’ heat hypersensitivity. Furthermore, the variation in the heat hypersensitivity of four RyR1 mutants highlights the complexity of MH. HICR likewise occurs in skeletal muscles of MH model mice. We propose that HICR contributes an additional positive feedback to accelerate thermogenesis in patients with MH.
