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Research ArticleArticle

Mice Expressing Regulators of G protein Signaling–insensitive Gαo Define Roles of μ Opioid Receptor Gαo and Gαi Subunit Coupling in Inhibition of Presynaptic GABA Release

Courtney A. Bouchet, Kylie B. McPherson, Ming-hua Li, John R. Traynor and Susan L. Ingram
Molecular Pharmacology September 2021, 100 (3) 217-223; DOI: https://doi.org/10.1124/molpharm.121.000249
Courtney A. Bouchet
Department of Neurologic Surgery, Oregon Health & Science University, Portland, Oregon (C.A.B., K.B.M., M.L., S.L.I.); and Department of Pharmacology and Edward F. Domino Research Center, Medical School, Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.R.T.)
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Kylie B. McPherson
Department of Neurologic Surgery, Oregon Health & Science University, Portland, Oregon (C.A.B., K.B.M., M.L., S.L.I.); and Department of Pharmacology and Edward F. Domino Research Center, Medical School, Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.R.T.)
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Ming-hua Li
Department of Neurologic Surgery, Oregon Health & Science University, Portland, Oregon (C.A.B., K.B.M., M.L., S.L.I.); and Department of Pharmacology and Edward F. Domino Research Center, Medical School, Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.R.T.)
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John R. Traynor
Department of Neurologic Surgery, Oregon Health & Science University, Portland, Oregon (C.A.B., K.B.M., M.L., S.L.I.); and Department of Pharmacology and Edward F. Domino Research Center, Medical School, Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.R.T.)
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Susan L. Ingram
Department of Neurologic Surgery, Oregon Health & Science University, Portland, Oregon (C.A.B., K.B.M., M.L., S.L.I.); and Department of Pharmacology and Edward F. Domino Research Center, Medical School, Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.R.T.)
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Abstract

Regulators of G protein signaling (RGS) proteins modulate signaling by G protein–coupled receptors. Using a knock-in transgenic mouse model with a mutation in Gαo that does not bind RGS proteins (RGS-insensitive), we determined the effect of RGS proteins on presynaptic μ opioid receptor (MOR)-mediated inhibition of GABA release in the ventrolateral periaqueductal gray (vlPAG). The MOR agonists [d-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) and met-enkephalin (ME) inhibited evoked inhibitory postsynaptic currents (eIPSCs) in the RGS-insensitive mice compared with wild-type (WT) littermates, respectively. Fentanyl inhibited eIPSCs similarly in both WT and RGS-insensitive mice. There were no differences in opioid agonist inhibition of spontaneous GABA release between the genotypes. To further probe the mechanism underlying these differences between opioid inhibition of evoked and spontaneous GABA release, specific myristoylated Gα peptide inhibitors for Gαo1 and Gαi1-3 that block receptor–G protein interactions were used to test the preference of agonists for MOR-Gα complexes. The Gαo1 inhibitor reduced DAMGO inhibition of eIPSCs, but Gαi1-3 inhibitors had no effect. Both Gαo1 and Gαi1-3 inhibitors separately reduced fentanyl inhibition of eIPSCs but had no effects on ME inhibition. Gαi1-3 inhibitors blocked the inhibitory effects of ME and fentanyl on miniature postsynaptic current (mIPSC) frequency, but both Gαo1 and Gαi1-3 inhibitors were needed to block the effects of DAMGO. Finally, baclofen-mediated inhibition of GABA release is unaffected in the RGS-insensitive mice and in the presence of Gαo1 and Gαi1-3 inhibitor peptides, suggesting that GABAB receptor coupling to G proteins in vlPAG presynaptic terminals is different than MOR coupling.

SIGNIFICANCE STATEMENT Presynaptic μ opioid receptors (MORs) in the ventrolateral periaqueductal gray are critical for opioid analgesia and are negatively regulated by RGS proteins. These data in RGS-insensitive mice provide evidence that MOR agonists differ in preference for Gαo versus Gαi and regulation by RGS proteins in presynaptic terminals, providing a mechanism for functional selectivity between agonists. The results further define important differences in MOR and GABAB receptor coupling to G proteins that could be exploited for new pain therapies.

Footnotes

    • Received January 27, 2021.
    • Accepted June 4, 2021.
  • This work was supported by National Institutes of Health National Institute on Drug Abuse [Grant R01DA035316 JRT and F31 DA052114 CAB].

  • The authors have no conflicts of interest.

  • https://doi.org/10.1124/molpharm.121.000249.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 100 (3)
Molecular Pharmacology
Vol. 100, Issue 3
1 Sep 2021
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Research ArticleArticle

Presynaptic MOR-RGS Regulation of GABA Release

Courtney A. Bouchet, Kylie B. McPherson, Ming-hua Li, John R. Traynor and Susan L. Ingram
Molecular Pharmacology September 1, 2021, 100 (3) 217-223; DOI: https://doi.org/10.1124/molpharm.121.000249

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Research ArticleArticle

Presynaptic MOR-RGS Regulation of GABA Release

Courtney A. Bouchet, Kylie B. McPherson, Ming-hua Li, John R. Traynor and Susan L. Ingram
Molecular Pharmacology September 1, 2021, 100 (3) 217-223; DOI: https://doi.org/10.1124/molpharm.121.000249
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