| First Author | McPherson KB | Year | 2018 |
| Journal | J Neurosci | Volume | 38 |
| Issue | 41 | Pages | 8737-8744 |
| PubMed ID | 30150362 | Mgi Jnum | J:266326 |
| Mgi Id | MGI:6202791 | Doi | 10.1523/JNEUROSCI.0516-18.2018 |
| Citation | McPherson KB, et al. (2018) Regulators of G-Protein Signaling (RGS) Proteins Promote Receptor Coupling to G-Protein-Coupled Inwardly Rectifying Potassium (GIRK) Channels. J Neurosci 38(41):8737-8744 |
| abstractText | Regulators of G-protein signaling (RGS) proteins negatively modulate presynaptic mu-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 Galphao proteins. mu-Opioid receptor agonist activation of GIRK currents was reduced for DAMGO and fentanyl but not for [Met(5)]-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 Galphao proteins in mu-opioid receptor and GABAB receptor signaling pathways in wild-type mice using myristoylated peptide inhibitors of Galphao1 and Galphai1-3 The results using these inhibitors indicate that receptor activation of GIRK channels is dependent on the preference of the agonist-stimulated receptor for Galphao versus that for Galphai. DAMGO and fentanyl-mediated GIRK currents were reduced in the presence of the Galphao1 inhibitor, but not the Galphai1-3 inhibitors. In contrast, the Galphao1 peptide inhibitor did not affect ME activation of GIRK currents, which is consistent with results in the Het mice, but the Galphai1-3 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.SIGNIFICANCE STATEMENT Regulators of G-protein signaling (RGS) proteins positively modulate GPCR coupling to GIRKs, and this coupling is critical for opioid- and baclofen-mediated spinal antinociception, whereas mu-opioid receptor-mediated supraspinal antinociception depends on presynaptic inhibition that is negatively regulated by RGS proteins. The identification of these opposite roles for RGS proteins has implications for signaling via other GPCRs. |
