PDF(Pubmed)
Abstract：
Transient receptor potential melastatin 8 (TRPM8) is a temperature- and menthol-sensitive ion channel that contributes to diverse physiological roles, including cold sensing and pain perception. Clinical trials targeting TRPM8 have faced repeated setbacks predominantly due to the knowledge gap in unraveling the molecular underpinnings governing polymodal activation. A better understanding of the molecular foundations between the TRPM8 activation modes may aid the development of mode-specific, thermal-neutral therapies. Ancestral sequence reconstruction was used to explore the origins of TRPM8 activation modes. By resurrecting key TRPM8 nodes along the human evolutionary trajectory, we gained valuable insights into the trafficking, stability, and function of these ancestral forms. Notably, this approach unveiled the differential emergence of cold and menthol sensitivity over evolutionary time, providing a fresh perspective on complex polymodal behavior. These studies provide a paradigm for understanding polymodal behavior in TRPM8 and other proteins with the potential to enhance our understanding of sensory receptor biology and pave the way for innovative therapeutic interventions.
摘要：
瞬时受体电位美司他丁8（TRPM8）是一种对温度和薄荷醇敏感的离子通道，具有多种生理作用，包括冷感知和疼痛感知。针对TRPM8的临床试验面临反复的挫折，主要是由于在解开控制多峰激活的分子基础方面的知识差距。更好地了解TRPM8激活模式之间的分子基础可能有助于模式特异性的发展，热中性疗法。祖先序列重建用于探索TRPM8激活模式的起源。通过沿着人类进化轨迹复活关键的TRPM8节点，我们获得了关于贩运的宝贵见解，稳定性,以及这些祖先形式的功能。值得注意的是,这种方法揭示了随着进化时间的推移，寒冷和薄荷醇敏感性的不同出现，为复杂的多模态行为提供了一个全新的视角。这些研究为理解TRPM8和其他蛋白质的多模态行为提供了范例，有可能增强我们对感觉受体生物学的理解，并为创新的治疗干预铺平道路。
