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Updated: Feb 24, 2026

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Inhibition of Transient Receptor Potential Melastatin 3 ion channels by G-protein βγ subunits

Doreen Badheka1, Yevgen Yudin1, Istvan Borbiro1

  • 1New Jersey Medical School, Rutgers, the State University of New Jersey, Newark, United States.

Elife
|August 23, 2017
PubMed

Insights

Activation of Gi/o-coupled receptors inhibits Transient Receptor Potential Melastatin 3 (TRPM3) channels. This novel signaling pathway involves Gβγ subunits directly regulating TRPM3 activity in neurons.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Ion Channel Physiology

Background:

  • Transient Receptor Potential Melastatin 3 (TRPM3) channels are key regulators of cellular excitability.
  • TRPM3 channels are activated by thermal stimuli and specific chemical ligands like pregnenolone sulphate (PregS) and CIM0216.
  • The precise regulatory mechanisms of TRPM3 channel activity remain incompletely understood.

Purpose of the Study:

  • To investigate the role of heterotrimeric G-proteins in the regulation of TRPM3 channel function.
  • To elucidate the specific subunits and mechanisms involved in Gi/o protein-mediated inhibition of TRPM3.
  • To explore the physiological relevance of this inhibitory pathway in neuronal signaling and nociception.

Main Methods:

  • Heterologous expression systems to study TRPM3 channel activity.
  • Patch-clamp electrophysiology to measure TRPM3 currents.
  • Co-immunoprecipitation assays to assess protein-protein interactions.
  • Calcium imaging in dorsal root ganglion (DRG) neurons.
  • In vivo behavioral studies in mice to assess nocifensive responses.

Main Results:

  • Activation of Gi/o-coupled receptors significantly inhibited TRPM3 channel activity.
  • Co-expression of Gβγ subunits, but not Gαi/o subunits, alleviated TRPM3 inhibition, suggesting a direct role for Gβγ.
  • TRPM3 channels directly co-immunoprecipitated with Gβ subunits.
  • Purified Gβγ proteins directly inhibited TRPM3 currents in excised patches.
  • Gi-coupled receptor agonists (baclofen, somatostatin) reduced TRPM3-mediated responses in DRG neurons and nocifensive behaviors in mice.

Conclusions:

  • TRPM3 channels are directly inhibited by Gβγ subunits of heterotrimeric G-proteins.
  • This represents a novel signaling mechanism controlling TRPM3 channel activity.
  • The findings provide new insights into the regulation of neuronal excitability and pain signaling pathways.
Keywords:
DRG neuronG-proteinTRPA1TRPM3TRPM8mouseneurosciencesensory ion channel

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