KCNQ1 is an essential mediator of the sex- dependent perception of moderate cold temperatures

• 成果类型: Article
• 署名作者: Kiper, Aytug K.; Wegner, Sven; Kadala, Aklesso; Rinne, Susanne; Schuette, Sven; Winter, Zoltan; Bertoune, Mirjam A. R.; Touska, Filip; Matschke, Veronika; Wrobel, Eva; Streit, Anne-Kathrin; Lang, Florian; Schmidt, Constanze; Schulze-Bahr, Eric; Schaefer, Martin K. - H.; Voelkl, Jakob; Seebohm, Guiscard; Zimmermann, Katharina; Decher, Niels
• 署名单位: Philipps University Marburg; Philipps University Marburg; University of Erlangen Nuremberg; Philipps University Marburg; Ruhr University Bochum; Ruhr University Bochum; Eberhard Karls University of Tubingen; Ruprecht Karls University Heidelberg; University of Munster; Johannes Kepler University Linz
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13937
• DOI: 10.1073/pnas.2322475121
• 发表日期: 2024-06-18
• 关键词: potassium channel; sensory neurons; in-vitro; trpm8; menthol; ion; sensitivity; activation; identification; stimulation

摘要

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 KCNQ1(-/-) mice displayed altered action potential firing properties. Strikingly, only male KCNQ1(-/-) mice showed substantial deficits in cold avoidance at moderately cold temperatures, with a strength of the phenotype similar to that observed in TRPM8(-/-) animals. While sex- dependent differences in thermal sensitivity have been well documented in humans and mice, KCNQ1 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.