Regulators of G-protein signaling (RGS) proteins promote receptor coupling to G-protein-coupled inwardly rectifying potassium (GIRK) channels

Kylie B. McPherson, Emily R. Leff, Minghua Li, Claire Meurice, Sherrica Tai, John R. Traynor, Susan L. Ingram

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Regulators of G-protein signaling (RGS) proteins negatively modulate presynaptic μ-opioid receptor inhibition of GABA release in the ventrolateral periaqueductal gray (vlPAG). Paradoxically, we find that G-protein-coupled receptor (GPCR) activation of G-protein-gated inwardly rectifying K+ channels (GIRKs) in the vlPAG is reduced in an agonist-and receptor-dependent manner in transgenic knock-in mice of either sex expressing mutant RGS-insensitive Gαo proteins. μ-Opioid receptor agonist activation of GIRK currents was reduced for DAMGO and fentanyl but not for [Met5]-enkephalin acetate salt hydrate (ME) in the RGS-insensitive heterozygous (Het) mice compared with wild-type mice. The GABAB agonist baclofen-induced GIRK currents were also reduced in the Het mice. We confirmed the role of Gαo proteins in μ-opioid receptor and GABAB receptor signaling pathways in wild-type mice using myristoylated peptide inhibitors of Gαo1 and Gαi1–3. The results using these inhibitors indicate that receptor activation of GIRK channels is dependent on the preference of the agonist-stimulated receptor for Gαo versus that for Gαi. DAMGO and fentanyl-mediated GIRK currents were reduced in the presence of the Gαo1 inhibitor, but not the Gαi1–3 inhibitors. In contrast, the Gαo1 peptide inhibitor did not affect ME activation of GIRK currents, which is consistent with results in the Het mice, but the Gαi1–3 inhibitors significantly reduced ME-mediated GIRK currents. Finally, the reduction in GIRK activation in the Het mice plays a role in opioid-and baclofen-mediated spinal antinociception, but not supraspinal antinociception. Thus, our studies indicate that RGS proteins have multiple mechanisms of modulating GPCR signaling that produce negative and positive regulation of signaling depending on the effector.

Original languageEnglish (US)
Pages (from-to)8737-8744
Number of pages8
JournalJournal of Neuroscience
Issue number41
StatePublished - Oct 10 2018


  • Analgesia
  • Descending pain pathway
  • GABA receptor
  • Opioids
  • Periqueductal gray
  • RGS proteins

ASJC Scopus subject areas

  • Neuroscience(all)


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