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

Marc Behrendt | Zendy; Fabian Gruss | Zendy; Raissa Enzeroth | Zendy; Sandeep Dembla | Zendy; Siyuan Zhao | Zendy; PierreAntoine Crassous | Zendy; Florian Mohr | Zendy; Mieke Nys | Zendy; Nikolaos Louros | Zendy; Rodrigo Gallardo | Zendy; Valentina Zorzini | Zendy; Doris Wagner | Zendy; Anastassios Economou | Zendy; Frédéric Rousseau | Zendy; Joost Schymkowitz | Zendy; Stephan Philipp | Zendy; Tibor Rohács | Zendy; Chris Ulens | Zendy; Johannes Oberwinkler | Zendy

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

Author(s) -

Marc Behrendt,

Fabian Gruss,

Raissa Enzeroth,

Sandeep Dembla,

Siyuan Zhao,

PierreAntoine Crassous,

Florian Mohr,

Mieke Nys,

Nikolaos Louros,

Rodrigo Gallardo,

Valentina Zorzini,

Doris Wagner,

Anastassios Economou,

Frédéric Rousseau,

Joost Schymkowitz,

Stephan Philipp,

Tibor Rohács,

Chris Ulens,

Johannes Oberwinkler

Publication year - 2020

Publication title -

proceedings of the national academy of sciences

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 5.011

H-Index - 771

eISSN - 1091-6490

pISSN - 0027-8424

DOI - 10.1073/pnas.2001177117

Subject(s) - inhibitory postsynaptic potential , ion channel , nociceptor , receptor , chemistry , microbiology and biotechnology , opioid , endogeny , g protein , neuroscience , biochemistry , biology , nociception

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 Gβ 1 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.

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