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

Proc Natl Acad Sci U S A. 2020 Nov 17;117(46):29090-29100. doi: 10.1073/pnas.2001177117. Epub 2020 Oct 29.


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.

Keywords: GPCR signaling; TRP channels; alternative splicing; opioid analgesia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Calcium / metabolism
  • GTP-Binding Protein beta Subunits / chemistry
  • GTP-Binding Protein beta Subunits / metabolism*
  • GTP-Binding Protein beta Subunits / pharmacology*
  • GTP-Binding Protein gamma Subunits / chemistry
  • GTP-Binding Protein gamma Subunits / metabolism*
  • GTP-Binding Protein gamma Subunits / pharmacology*
  • HEK293 Cells
  • Humans
  • Hyperalgesia / metabolism
  • Models, Molecular
  • Mutation
  • Neurons / metabolism
  • Pain / metabolism
  • Receptors, Opioid / metabolism
  • TRPM Cation Channels / chemistry*
  • TRPM Cation Channels / drug effects*
  • TRPM Cation Channels / genetics
  • TRPM Cation Channels / metabolism*


  • G-protein Beta gamma
  • GTP-Binding Protein beta Subunits
  • GTP-Binding Protein gamma Subunits
  • Receptors, Opioid
  • TRPM Cation Channels
  • TRPM3 protein, human
  • Calcium