Structural dynamics at cytosolic inter-protomer interfaces control gating of a mammalian TRPM5 channel

The Transient Receptor Potential Melastatin (TRPM) family of tetrameric cation channels is involved in a wide range of biological functions, from sensory perception to cardiac function. 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 desensitization. Structures of rat TRPM5 identify a series of conformational transitions triggered by Ca2+ binding. These transitions involve formation and dissolution of cytoplasmic inter-protomer interfaces, where the MHR1/2 domain and the rib helix play important roles. 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.