Institute for Physiology and Pathophysiology, Department of Vegetative Physiology and Center for Mind, Brain and Behavior, Philipps-University Marburg, 35032 Marburg, Germany.
Department of Anesthesiology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany.
Proc Natl Acad Sci U S A. 2024 Jun 18;121(25):e2322475121. doi: 10.1073/pnas.2322475121. Epub 2024 Jun 10.
Low temperatures and cooling agents like menthol induce cold sensation by activating the peripheral cold receptors TRPM8 and TRPA1, cation channels belonging to the TRP channel family, while the reduction of potassium currents provides an additional and/or synergistic mechanism of cold sensation. Despite extensive studies over the past decades to identify the molecular receptors that mediate thermosensation, cold sensation is still not fully understood and many cold-sensitive peripheral neurons do not express the well-established cold sensor TRPM8. We found that the voltage-gated potassium channel KCNQ1 (Kv7.1), which is defective in cardiac LQT1 syndrome, is, in addition to its known function in the heart, a highly relevant and sex-specific sensor of moderately cold temperatures. We found that KCNQ1 is expressed in skin and dorsal root ganglion neurons, is sensitive to menthol and cooling agents, and is highly sensitive to moderately cold temperatures, in a temperature range at which TRPM8 is not thermosensitive. C-fiber recordings from mice displayed altered action potential firing properties. Strikingly, only male mice showed substantial deficits in cold avoidance at moderately cold temperatures, with a strength of the phenotype similar to that observed in animals. While sex-dependent differences in thermal sensitivity have been well documented in humans and mice, is the first gene reported to play a role in sex-specific temperature sensation. Moreover, we propose that KCNQ1, together with TRPM8, is a key instrumentalist that orchestrates the range and intensity of cold sensation.
低温和薄荷醇等冷却剂通过激活属于 TRP 通道家族的外周冷受体 TRPM8 和 TRPA1，阳离子通道来引起冷感，而钾电流的减少则提供了冷感的额外和/或协同机制。尽管在过去的几十年中进行了广泛的研究来确定介导热感觉的分子受体，但对冷感觉的了解仍不全面，许多冷敏感的外周神经元并不表达已确立的冷传感器 TRPM8。我们发现，电压门控钾通道 KCNQ1（Kv7.1）在心脏 LQT1 综合征中存在缺陷，除了其在心脏中的已知功能外，还是中度低温的高度相关且具有性别特异性的传感器。我们发现 KCNQ1 在皮肤和背根神经节神经元中表达，对薄荷醇和冷却剂敏感，并且对 TRPM8 不敏感的温度范围内对中度低温高度敏感。来自 小鼠的 C 纤维记录显示动作电位发射特性发生改变。引人注目的是，只有雄性 小鼠在中度低温下表现出明显的冷回避缺陷，其表型强度与在 动物中观察到的相似。虽然人类和小鼠中的热敏感性的性别差异已有充分记录，但 是第一个被报道在性别特异性温度感觉中起作用的基因。此外，我们提出 KCNQ1 与 TRPM8 一起，是协调冷感范围和强度的关键工具。
