美国加州大学David Julius团队研究出冷敏感性的结构能量学。这一研究成果发表在2026年3月25日出版的国际学术期刊《自然》上。

在这里，研究组通过结合低温电子显微镜和氢-氘交换质谱来阐明冷诱发激活TRPM8的机制，从而缩小了这一差距。首先，该研究组可视化细胞膜中的TRPM8通道，在那里真正的薄荷醇和冷诱发的开放状态被捕获。该研究团队还发现了一种新的“半交换”结构，在这种结构中，随着S6跨膜螺旋和孔区元素的重新定位，通道亚单元的交错被重新排列。

然后，小组使用氢-氘交换质谱法来确定孔隙和TRP螺旋是表现出最大刺激引起的驱动通道门控的能量变化的区域。具体来说，冷诱发的外孔区域稳定重新定位了S6跨膜螺旋孔内衬，同时使调节脂质结合以稳定开放通道。通过将人类TRPM8与对薄荷醇敏感但对冷不敏感的鸟类同源基因进行比较，验证了与激活相关的结构机制。该课题组研究人员提出了一种自由能景观和构象途径，即冷或冷却剂激活这种热感觉受体。

据介绍，热敏瞬时受体电位（TRP）离子通道使体感神经纤维能够在广泛的生理范围内检测其热环境的变化。在哺乳动物中，薄荷醇受体TRPM8在温度低于26℃时被激活，对感知冷或化学冷却剂至关重要。一个令人着迷但尚未实现的目标是阐明结构和热力学机制，即TRPM8或其他热敏通道通过环境温度变化进行门控。最近以低温电子显微镜为主题的研究试图解决这个具有挑战性的问题，但由于难以可视化温度诱发的构象亚态或评估控制门控转变的能量景观。

附：英文原文

Title: Structural energetics of cold sensitivity

Author: Choi, Kevin Y., Lin, Xiaoxuan, Cheng, Yifan, Julius, David

Issue&Volume: 2026-03-25

Abstract: Thermosensitive transient receptor potential (TRP) ion channels enable somatosensory nerve fibres to detect changes in our thermal environment over a wide physiologic range1,2,3. In mammals, the menthol receptor, TRPM8, is activated by temperatures below approximately 26°C and is essential for the perception of cold or chemical cooling agents4,5,6. A fascinating, yet still unachieved goal is to elucidate mechanisms, both structural and thermodynamic, whereby TRPM8 or other thermosensitive channels are gated by changes in ambient temperature. Recent studies using cryogenic electron microscopy have attempted to address this challenging question but are limited by difficulties in visualizing temperature-evoked conformational sub-states or assessing the energetic landscape governing gating transitions7,8. Here we close this gap by combining cryogenic electron microscopy with hydrogen–deuterium exchange mass spectrometry to elucidate a mechanism for cold-evoked activation of TRPM8. First, we visualize TRPM8 channels in cellular membranes, where bona fide menthol- and cold-evoked open states are captured. We also identify a new ‘semi-swapped’ architecture in which interdigitation of channel sub-units is rearranged substantially following repositioning of the S6 transmembrane helix and elements of the pore region. We then use hydrogen–deuterium exchange mass spectrometry to pinpoint the pore and TRP helices as the regions exhibiting the greatest stimulus-evoked energetic changes that drive channel gating. Specifically, cold-evoked stabilization of the outer pore region repositions the pore lining S6 transmembrane helix while enabling binding of a regulatory lipid to stabilize the open channel. Structural mechanisms associated with activation are validated by comparison of human TRPM8 with the menthol-sensitive but relatively cold-insensitive avian orthologue. We propose a free energy landscape and conformational pathway whereby cold or cooling agents activate this thermosensory receptor.

DOI: 10.1038/s41586-026-10276-2

Source: https://www.nature.com/articles/s41586-026-10276-2