Cellular heat-sensing is a universal strategy for avoiding thermal damage and adapting to environments by regulating thermogenic activities. If heat-sensing results in the acceleration of processes governing cellular thermogenesis, hyperthermia can occur. However, how this positive feedback loop contributes to hyperthermia development, especially the gap between heat-sensing and thermogenesis, remains largely unknown. Here, we show that an optically controlled local heat pulse induces an intracellular Ca²⁺ burst in cultured HEK 293 cells overexpressing ryanodine-receptor-type-1 (RyR1) mutants related to the life-threatening illness malignant hyperthermia (MH), and that the Ca²⁺ burst originates from heat-induced Ca²⁺-release (HICR) because of the mutant channels' heat hypersensitivity. Furthermore, the heat hypersensitivity of the four RyR1 mutants was ranked, highlighting the complexity of MH. Our findings reveal the novel cellular heat-sensing mechanism, HICR, is essential for the functional positive feedback loop causing MH, suggesting a well-tuned HICR is fundamental for heat-mediated intracellular signaling.

中文翻译：

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ryanodine 1型受体突变体的热超敏反应与恶性高热有关

细胞热感是一种通用的策略，可通过调节生热活动来避免热损伤并适应环境。如果热感应导致控制细胞生热的过程加速，则会发生体温过高。然而，这种正反馈回路如何促进热疗的发展，尤其是热敏和生热之间的差距，仍然是未知的。在这里，我们表明，受光控制的局部热脉冲在过度表达与威胁生命的疾病恶性高热（MH）相关的ryanodine-receptor-type-1（RyR1）突变型的培养的HEK 293细胞中诱导细胞内Ca ²⁺爆发，并且Ca ²⁺爆发源自热诱导的Ca ²⁺释放（HICR），因为突变体通道的热超敏性。此外，对四个RyR1突变体的热超敏性进行了排名，突出了MH的复杂性。我们的发现揭示了新颖的细胞热感应机制HICR对于导致MH的功能性正反馈回路至关重要，这表明精心调校的HICR对于热介导的细胞内信号传导至关重要。