The transient receptor potential melastatin (TRPM) tetrameric cation channels are involved in a wide range of biological functions, from temperature sensing and taste transduction to regulation of cardiac function, inflammatory pain, and insulin secretion. The structurally conserved TRPM cytoplasmic domains make up >70 % of the total protein. To investigate the mechanism by which the TRPM cytoplasmic domains contribute to gating, we employed electrophysiology and cryo-EM to study TRPM5—a channel that primarily relies on activation via intracellular Ca 2+ . Here, we show that activation of mammalian TRPM5 channels is strongly altered by Ca 2+ -dependent desensitization. Structures of rat TRPM5 identify a series of conformational transitions triggered by Ca 2+ binding, whereby formation and dissolution of cytoplasmic interprotomer interfaces appear to control activation and desensitization of the channel. This study shows the importance of the cytoplasmic assembly in TRPM5 channel function and sets the stage for future investigations of other members of the TRPM family.

中文翻译：

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胞质原体间界面的结构动力学控制哺乳动物 TRPM5 通道的门控


瞬态受体电位褪黑素 (TRPM) 四聚体阳离子通道涉及广泛的生物功能，从温度传感和味觉传导到心脏功能、炎症疼痛和胰岛素分泌的调节。结构保守的 TRPM 胞质结构域占总蛋白的 70% 以上。为了研究 TRPM 胞质结构域参与门控的机制，我们采用电生理学和冷冻电镜来研究 TRPM5——一种主要依赖于细胞内 Ca 2+ 激活的通道。在这里，我们发现哺乳动物 TRPM5 通道的激活受到 Ca 2+ 依赖性脱敏的强烈改变。大鼠TRPM5的结构识别出一系列由Ca 2+ 结合触发的构象转变，由此细胞质原体间界面的形成和溶解似乎控制通道的激活和脱敏。这项研究表明了细胞质组装在 TRPM5 通道功能中的重要性，并为 TRPM 家族其他成员的未来研究奠定了基础。