College of Wildlife and Protected Area, Northeast Forestry University, 150040 Harbin, China.
Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences, Kunming, 650223 China.
Proc Natl Acad Sci U S A. 2022 May 24;119(21):e2201349119. doi: 10.1073/pnas.2201349119. Epub 2022 May 20.
To cope with temperature fluctuations, molecular thermosensors in animals play a pivotal role in accurately sensing ambient temperature. Transient receptor potential melastatin 8 (TRPM8) is the most established cold sensor. In order to understand how the evolutionary forces bestowed TRPM8 with cold sensitivity, insights into both emergence of cold sensing during evolution and the thermodynamic basis of cold activation are needed. Here, we show that the trpm8 gene evolved by forming and regulating two domains (MHR1-3 and pore domains), thus determining distinct cold-sensitive properties among vertebrate TRPM8 orthologs. The young trpm8 gene without function can be observed in the closest living relatives of tetrapods (lobe-finned fishes), while the mature MHR1-3 domain with independent cold sensitivity has formed in TRPM8s of amphibians and reptiles to enable channel activation by cold. Furthermore, positive selection in the TRPM8 pore domain that tuned the efficacy of cold activation appeared late among more advanced terrestrial tetrapods. Interestingly, the mature MHR1-3 domain is necessary for the regulatory mechanism of the pore domain in TRPM8 cold activation. Our results reveal the domain-based evolution for TRPM8 functions and suggest that the acquisition of cold sensitivity in TRPM8 facilitated terrestrial adaptation during the water-to-land transition.
为了应对温度波动，动物中的分子温度传感器在准确感知环境温度方面起着关键作用。瞬时受体电位 melastatin 8 (TRPM8) 是最成熟的冷传感器。为了了解进化力量如何赋予 TRPM8 冷敏性，需要了解冷感在进化过程中的出现以及冷激活的热力学基础。在这里，我们表明 trpm8 基因通过形成和调节两个结构域（MHR1-3 和孔结构域）而进化，从而决定了脊椎动物 TRPM8 同源物中独特的冷敏特性。在四足动物（肉鳍鱼）的最近亲中可以观察到没有功能的年轻 trpm8 基因，而在两栖动物和爬行动物的 TRPM8 中已经形成了具有独立冷敏感性的成熟 MHR1-3 结构域，从而能够通过冷激活通道。此外，在更高级的陆地四足动物中，调节冷激活功效的 TRPM8 孔结构域中的正选择出现较晚。有趣的是，成熟的 MHR1-3 结构域对于 TRPM8 冷激活中孔结构域的调节机制是必要的。我们的研究结果揭示了 TRPM8 功能的基于结构域的进化，并表明在从水生到陆地的过渡过程中，TRPM8 中冷敏感性的获得促进了陆地适应。
