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Molecular Pharmacology

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Rapid CommunicationAccelerated Communication

Direct Coupling of a Seven-Transmembrane-Span Receptor to a Gαi G-Protein Regulatory Motif Complex

William G. Robichaux III, Sukru S. Oner, Stephen M. Lanier and Joe B. Blumer
Molecular Pharmacology August 2015, 88 (2) 231-237; DOI: https://doi.org/10.1124/mol.115.097741
William G. Robichaux III
Department of Cell and Molecular Pharmacology and Experimental Therapeutics (W.G.R., S.S.O., S.M.L., J.B.B.) and Department of Neurosciences (J.B.B.), Medical University of South Carolina, Charleston, South Carolina
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Sukru S. Oner
Department of Cell and Molecular Pharmacology and Experimental Therapeutics (W.G.R., S.S.O., S.M.L., J.B.B.) and Department of Neurosciences (J.B.B.), Medical University of South Carolina, Charleston, South Carolina
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Stephen M. Lanier
Department of Cell and Molecular Pharmacology and Experimental Therapeutics (W.G.R., S.S.O., S.M.L., J.B.B.) and Department of Neurosciences (J.B.B.), Medical University of South Carolina, Charleston, South Carolina
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Joe B. Blumer
Department of Cell and Molecular Pharmacology and Experimental Therapeutics (W.G.R., S.S.O., S.M.L., J.B.B.) and Department of Neurosciences (J.B.B.), Medical University of South Carolina, Charleston, South Carolina
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Abstract

Group II activator of G-protein signaling (AGS) proteins contain one or more G-protein regulatory motifs (GPR), which serve as docking sites for GαiGDP independent of Gβγ and stabilize the GDP-bound conformation of Gαi, acting as guanine nucleotide dissociation inhibitors. The GαGPR interaction is regulated by seven-transmembrane-spanning (7TM) receptors in the intact cell as determined by bioluminescence resonance energy transfer (BRET). It is hypothesized that a 7TM receptor directly couples to the GαGPR complex in a manner analogous to receptor coupling to the Gαβγ heterotrimer. As an initial approach to test this hypothesis, we used BRET to examine 7TM receptor–mediated regulation of GαGPR in the intact cell when Gαi2 yellow fluorescent protein (YFP) was tethered to the carboxyl terminus of the α2A adrenergic receptor (α2AAR-Gαi2YFP). AGS3– and AGS4–Renilla luciferase (Rluc) exhibited robust BRET with the tethered GαiYFP, and this interaction was regulated by receptor activation localizing the regulation to the receptor microenvironment. Agonist regulation of the receptor-Gαi-GPR complex was also confirmed by coimmunoprecipitation and cell fractionation. The tethered Gαi2 was rendered pertussis toxin–insensitive by a C352I mutation, and receptor coupling to endogenous Gαi/oβγ was subsequently eliminated by cell treatment with pertussis toxin (PT). Basal and agonist-induced regulation of α2AAR-Gαi2YFPC352I:AGS3Rluc and α2AAR-Gαi2YFPC352I:AGS4Rluc BRET was not altered by PT treatment or Gβγ antagonists. Thus, the localized regulation of GαGPR by receptor activation appears independent of endogenous Gαi/oβγ, suggesting that GαiAGS3 and GαiAGS4 directly sense agonist-induced conformational changes in the receptor, as is the case for 7TM receptor coupling to the Gαβγ heterotrimer. The direct coupling of a receptor to the GαiGPR complex provides an unexpected platform for signal propagation with broad implications.

Footnotes

    • Received January 8, 2015.
    • Accepted May 12, 2015.
  • ↵1 Current affiliation: Istanbul Medeniyet University, Goztepe Research and Training Hospital, Istanbul, Turkey.

  • ↵2 Current affiliation: Department of Pharmacology, Wayne State University, Detroit, Michigan.

  • This work was supported by the National Institutes of Health National Institute for General Medical Sciences [Grant R01-GM086510 to J.B.B.], the National Institutes of Health National Institute for Neurologic Diseases and Stroke [Grant R01-NS24821 to S.M.L.], and the National Institutes of Health National Institute for Drug Abuse [Grant R01-DA025896 to S.M.L.].

  • dx.doi.org/10.1124/mol.115.097741.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 88 (2)
Molecular Pharmacology
Vol. 88, Issue 2
1 Aug 2015
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Rapid CommunicationAccelerated Communication

Direct Coupling of a 7TM Receptor to GαiGPR

William G. Robichaux, Sukru S. Oner, Stephen M. Lanier and Joe B. Blumer
Molecular Pharmacology August 1, 2015, 88 (2) 231-237; DOI: https://doi.org/10.1124/mol.115.097741

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Rapid CommunicationAccelerated Communication

Direct Coupling of a 7TM Receptor to GαiGPR

William G. Robichaux, Sukru S. Oner, Stephen M. Lanier and Joe B. Blumer
Molecular Pharmacology August 1, 2015, 88 (2) 231-237; DOI: https://doi.org/10.1124/mol.115.097741
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