研究人员表示，TRPM8（transient receptor potential melastatin 8）通道是负责哺乳动物由薄荷和寒冷引起凉爽感觉的主要分子转换器。TRPM8的激活是由降温化合物和膜脂质磷脂酰肌醇4,5-二磷酸（PIP2）共同控制。通过了解降温激动剂和PIP2依赖性的TRPM8激活的结构基础，人们对冷感的认识以及TRPM8对神经炎症和疼痛的治疗潜力将得到加强。
研究人员展示了小鼠TRPM8在封闭、中间和开放状态下沿配体和PIP2依赖的门控途径的冷冻电镜结构。研究结果发现了两个不连续的激动剂位点，门控位置的状态依赖性重排，以及门控形成的S6的无序到有序的转变，从而阐明了哺乳动物中化学诱导凉感的分子基础。
附：英文原文
Title: Activation mechanism of the mouse cold-sensing TRPM8 channel by cooling agonist and PIP2
Author: Ying Yin, Feng Zhang, Shasha Feng, Kevin John Butay, Mario J. Borgnia, Wonpil Im, Seok-Yong Lee
Issue&Volume: 2022-10-14
Abstract: The transient receptor potential melastatin 8 (TRPM8) channel is the primary molecular transducer responsible for the cool sensation elicited by menthol and cold in mammals. TRPM8 activation is controlled by cooling compounds together with the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2). Our knowledge of cold sensation and the therapeutic potential of TRPM8 for neuroinflammatory diseases and pain will be enhanced by understanding the structural basis of cooling agonist- and PIP2-dependent TRPM8 activation. We present cryo–electron microscopy structures of mouse TRPM8 in closed, intermediate, and open states along the ligand- and PIP2-dependent gating pathway. Our results uncover two discrete agonist sites, state-dependent rearrangements in the gate positions, and a disordered-to-ordered transition of the gate-forming S6—elucidating the molecular basis of chemically induced cool sensation in mammals.
DOI: add1268
Source: https://www.science.org/doi/10.1126/science.add1268