| Literature DB >> 33122432 |
Marc Behrendt1,2, Fabian Gruss3, Raissa Enzeroth1,2, Sandeep Dembla1,2, Siyuan Zhao4, Pierre-Antoine Crassous4, Florian Mohr1, Mieke Nys3, Nikolaos Louros5, Rodrigo Gallardo5, Valentina Zorzini6, Doris Wagner1, Anastassios Economou6, Frederic Rousseau5, Joost Schymkowitz5, Stephan E Philipp7, Tibor Rohacs4, Chris Ulens8, Johannes Oberwinkler9,2.
Abstract
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.Entities:
Keywords: GPCR signaling; TRP channels; alternative splicing; opioid analgesia
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Year: 2020 PMID： 33122432 PMCID： PMC7682392 DOI： 10.1073/pnas.2001177117
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 12.779