The structural basis for an on-off switch controlling Gβγ-mediated inhibition of TRPM3 channels.

Proceedings of the National Academy of Sciences of the United States of America 2020 Nov 17

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TRPM3 channels play important roles in the detection of noxious heat and in inflammatory thermal hyperalgesia. The activity of these ion channels in somatosensory neurons is tightly regulated by µ-opioid receptors through the signaling of Gβγ proteins, thereby reducing TRPM3-mediated pain. We show here that Gβγ directly binds to a domain of 10 amino acids in TRPM3 and solve a cocrystal structure of this domain together with Gβγ. Using these data and mutational analysis of full-length proteins, we pinpoint three amino acids in TRPM3 and their interacting partners in Gβ1 that are individually necessary for TRPM3 inhibition by Gβγ. The 10-amino-acid Gβγ-interacting domain in TRPM3 is subject to alternative splicing. Its inclusion in or exclusion from TRPM3 channel proteins therefore provides a mechanism for switching on or off the inhibitory action that Gβγ proteins exert on TRPM3 channels.

Citation

Marc Behrendt, Fabian Gruss, Raissa Enzeroth, Sandeep Dembla, Siyuan Zhao, Pierre-Antoine Crassous, Florian Mohr, Mieke Nys, Nikolaos Louros, Rodrigo Gallardo, Valentina Zorzini, Doris Wagner, Anastassios Economou, Frederic Rousseau, Joost Schymkowitz, Stephan E Philipp, Tibor Rohacs, Chris Ulens, Johannes Oberwinkler. The structural basis for an on-off switch controlling Gβγ-mediated inhibition of TRPM3 channels. Proceedings of the National Academy of Sciences of the United States of America. 2020 Nov 17;117(46):29090-29100