Abstract：
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 Ca2+. Here, we show that activation of mammalian TRPM5 channels is strongly altered by Ca2+-dependent desensitization. Structures of rat TRPM5 identify a series of conformational transitions triggered by Ca2+ 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.
摘要：
瞬时受体电位美司他丁(TRPM)四聚体阳离子通道参与了广泛的生物学功能,从温度传感和味觉转导到心脏功能的调节，炎性疼痛，和胰岛素分泌。结构保守的TRPM细胞质结构域占总蛋白的>70%。为了研究TRPM细胞质结构域有助于门控的机制，我们采用电生理学和低温EM来研究TRPM5-一种主要依赖于通过细胞内Ca2+激活的通道。这里,我们表明，哺乳动物TRPM5通道的激活被Ca2依赖性脱敏强烈改变。大鼠TRPM5的结构确定了一系列由Ca2+结合触发的构象转变，因此，细胞质间质界面的形成和溶解似乎可以控制通道的激活和脱敏。这项研究显示了细胞质组装在TRPM5通道功能中的重要性，并为将来对TRPM家族其他成员的研究奠定了基础。
