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Molecular Pharmacology

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Research ArticleArticle

Differential Effects of the Gβ5-RGS7 Complex on Muscarinic M3 Receptor–Induced Ca2+ Influx and Release

Darla Karpinsky-Semper, Claude-Henry Volmar, Shaun P. Brothers and Vladlen Z. Slepak
Molecular Pharmacology May 2014, 85 (5) 758-768; DOI: https://doi.org/10.1124/mol.114.091843
Darla Karpinsky-Semper
Department of Molecular and Cellular Pharmacology (D.K.-S., V.Z.S.) and Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences (C.-H.V., S.P.B.), University of Miami Miller School of Medicine, Miami, Florida
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Claude-Henry Volmar
Department of Molecular and Cellular Pharmacology (D.K.-S., V.Z.S.) and Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences (C.-H.V., S.P.B.), University of Miami Miller School of Medicine, Miami, Florida
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Shaun P. Brothers
Department of Molecular and Cellular Pharmacology (D.K.-S., V.Z.S.) and Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences (C.-H.V., S.P.B.), University of Miami Miller School of Medicine, Miami, Florida
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Vladlen Z. Slepak
Department of Molecular and Cellular Pharmacology (D.K.-S., V.Z.S.) and Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences (C.-H.V., S.P.B.), University of Miami Miller School of Medicine, Miami, Florida
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Abstract

The G protein β subunit Gβ5 uniquely forms heterodimers with R7 family regulators of G protein signaling (RGS) proteins (RGS6, RGS7, RGS9, and RGS11) instead of Gγ. Although the Gβ5-RGS7 complex attenuates Ca2+ signaling mediated by the muscarinic M3 receptor (M3R), the route of Ca2+ entry (i.e., release from intracellular stores and/or influx across the plasma membrane) is unknown. Here, we show that, in addition to suppressing carbachol-stimulated Ca2+ release, Gβ5-RGS7 enhanced Ca2+ influx. This novel effect of Gβ5-RGS7 was blocked by nifedipine and 2-aminoethoxydiphenyl borate. Experiments with pertussis toxin, an RGS domain–deficient mutant of RGS7, and UBO-QIC {L-threonine,(3R)-N-acetyl-3-hydroxy-L-leucyl-(aR)-a-hydroxybenzenepropanoyl-2,3-idehydro-N-methylalanyl-L-alanyl-N-methyl-L-alanyl-(3R)-3-[[(2S,3R)-3-hydroxy-4- methyl-1-oxo-2-[(1-oxopropyl)amino]pentyl]oxy]-L-leucyl-N,O-dimethyl-,(7→1)-lactone (9CI)}, a novel inhibitor of Gq, showed that Gβ5-RGS7 modulated a Gq-mediated pathway. These studies indicate that Gβ5-RGS7, independent of RGS7 GTPase-accelerating protein activity, couples M3R to a nifedipine-sensitive Ca2+ channel. We also compared the action of Gβ5-RGS7 on M3R-induced Ca2+ influx and release elicited by different muscarinic agonists. Responses to Oxo-M [oxotremorine methiodide N,N,N,-trimethyl-4-(2-oxo-1-pyrrolidinyl)-2-butyn-1-ammonium iodide] were insensitive to Gβ5-RGS7. Pilocarpine responses consisted of a large release and modest influx components, of which the former was strongly inhibited whereas the latter was insensitive to Gβ5-RGS7. McN-A-343 [(4-hydroxy-2-butynyl)-1-trimethylammonium-3-chlorocarbanilate chloride] was the only compound whose total Ca2+ response was enhanced by Gβ5-RGS7, attributed to, in part, by the relatively small Ca2+ release this partial agonist stimulated. Together, these results show that distinct agonists not only have differential M3R functional selectivity, but also confer specific sensitivity to the Gβ5-RGS7 complex.

Footnotes

    • Received January 22, 2014.
    • Accepted February 28, 2014.
  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM060019] and an American Heart Association Predoctoral fellowship [10PRE3600004].

  • dx.doi.org/10.1124/mol.114.091843.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 85 (5)
Molecular Pharmacology
Vol. 85, Issue 5
1 May 2014
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Research ArticleArticle

Effect of Gβ5-RGS7 on Muscarinic M3 Receptor Ca2+ Signaling

Darla Karpinsky-Semper, Claude-Henry Volmar, Shaun P. Brothers and Vladlen Z. Slepak
Molecular Pharmacology May 1, 2014, 85 (5) 758-768; DOI: https://doi.org/10.1124/mol.114.091843

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Research ArticleArticle

Effect of Gβ5-RGS7 on Muscarinic M3 Receptor Ca2+ Signaling

Darla Karpinsky-Semper, Claude-Henry Volmar, Shaun P. Brothers and Vladlen Z. Slepak
Molecular Pharmacology May 1, 2014, 85 (5) 758-768; DOI: https://doi.org/10.1124/mol.114.091843
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