G protein βγ subunits inhibit TRPM3 ion channels in sensory neurons

Elife. 2017 Aug 15:6:e26138. doi: 10.7554/eLife.26138.

Abstract

Transient receptor potential (TRP) ion channels in peripheral sensory neurons are functionally regulated by hydrolysis of the phosphoinositide PI(4,5)P2 and changes in the level of protein kinase mediated phosphorylation following activation of various G protein coupled receptors. We now show that the activity of TRPM3 expressed in mouse dorsal root ganglion (DRG) neurons is inhibited by agonists of the Gi-coupled µ opioid, GABA-B and NPY receptors. These agonist effects are mediated by direct inhibition of TRPM3 by Gβγ subunits, rather than by a canonical cAMP mediated mechanism. The activity of TRPM3 in DRG neurons is also negatively modulated by tonic, constitutive GPCR activity as TRPM3 responses can be potentiated by GPCR inverse agonists. GPCR regulation of TRPM3 is also seen in vivo where Gi/o GPCRs agonists inhibited and inverse agonists potentiated TRPM3 mediated nociceptive behavioural responses.

Keywords: DRG; GPCR; TRP channels; ion channels; mouse; neuroscience; pain; sensory neuron.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / antagonists & inhibitors
  • Animals
  • Baclofen / antagonists & inhibitors
  • CHO Cells
  • Calcium / analysis
  • Capsaicin
  • Cricetulus
  • Electrophysiology / methods
  • Female
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • GTP-Binding Protein beta Subunits / antagonists & inhibitors*
  • GTP-Binding Protein gamma Subunits / antagonists & inhibitors*
  • Ganglia, Spinal / metabolism
  • HEK293 Cells
  • Humans
  • Ion Channels / drug effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Morphine / antagonists & inhibitors
  • Pain / metabolism
  • Pain Measurement
  • Phosphatidylinositols / metabolism
  • Receptor, Cannabinoid, CB1 / agonists
  • Sensory Receptor Cells / drug effects*
  • TRPM Cation Channels / drug effects*
  • TRPM Cation Channels / genetics
  • TRPM Cation Channels / metabolism

Substances

  • Analgesics, Opioid
  • G-protein Beta gamma
  • GTP-Binding Protein beta Subunits
  • GTP-Binding Protein gamma Subunits
  • Ion Channels
  • Phosphatidylinositols
  • Receptor, Cannabinoid, CB1
  • TRPM Cation Channels
  • TRPM3 protein, mouse
  • Morphine
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Baclofen
  • Capsaicin
  • Calcium