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Regulation of Gbetagamma^sub i^-Dependent PLC-beta3 Activity in Smooth Muscle: Inhibitory Phosphorylation of PLC-beta3 by PKA and PKG and Stimulatory Phosphorylation of Galpha^sub i^-GTPase-Activating Protein RGS2 by PKG
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Regulation of Gbetagamma^sub i^-Dependent PLC-beta3 Activity in Smooth Muscle: Inhibitory Phosphorylation of PLC-beta3 by PKA and PKG and Stimulatory Phosphorylation of Galpha^sub i^-GTPase-Activating Protein RGS2 by PKG
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Regulation of Gbetagamma^sub i^-Dependent PLC-beta3 Activity in Smooth Muscle: Inhibitory Phosphorylation of PLC-beta3 by PKA and PKG and Stimulatory Phosphorylation of Galpha^sub i^-GTPase-Activating Protein RGS2 by PKG
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Journal Article
Regulation of Gbetagamma^sub i^-Dependent PLC-beta3 Activity in Smooth Muscle: Inhibitory Phosphorylation of PLC-beta3 by PKA and PKG and Stimulatory Phosphorylation of Galpha^sub i^-GTPase-Activating Protein RGS2 by PKG
2014
Overview
In gastrointestinal smooth muscle, agonists that bind to G^sub i^-coupled receptors activate preferentially PLC-[beta]3 via G[beta]γ to stimulate phosphoinositide (PI) hydrolysis and generate inositol 1,4,5-trisphosphate (IP^sub 3^) leading to IP^sub 3^-dependent Ca^sup 2+^ release and muscle contraction. In the present study, we identified the mechanism of inhibition of PLC-[beta]3-dependent PI hydrolysis by cAMP-dependent protein kinase (PKA) and cGMP-dependent protein kinase (PKG). Cyclopentyl adenosine (CPA), an adenosine A^sub 1^ receptor agonist, caused an increase in PI hydrolysis in a concentration-dependent fashion; stimulation was blocked by expression of the carboxyl-terminal sequence of GRK2(495-689), a G[beta]γ-scavenging peptide, or G[alpha]^sub i^ minigene but not G[alpha]^sub q^ minigene. Isoproterenol and S-nitrosoglutathione (GSNO) induced phosphorylation of PLC-[beta]3 and inhibited CPA-induced PI hydrolysis, Ca^sup 2+^ release, and muscle contraction. The effect of isoproterenol on all three responses was inhibited by PKA inhibitor, myristoylated PKI, or AKAP inhibitor, Ht-31, whereas the effect of GSNO was selectively inhibited by PKG inhibitor, Rp-cGMPS. GSNO, but not isoproterenol, also phosphorylated G[alpha]^sub i^-GTPase-activating protein, RGS2, and enhanced association of G[alpha]^sub i3^-GTP and RGS2. The effect of GSNO on PI hydrolysis was partly reversed in cells (i) expressing constitutively active GTPase-resistant G[alpha]^sub i^ mutant (Q204L), (ii) phosphorylation-site-deficient RGS2 mutant (S46A/S64A), or (iii) siRNA for RGS2. We conclude that PKA and PKG inhibit G[beta]γ^sub i^-dependent PLC-[beta]3 activity by direct phosphorylation of PLC-[beta]3. PKG, but not PKA, also inhibits PI hydrolysis indirectly by a mechanism involving phosphorylation of RGS2 and its association with G[alpha]^sub i^-GTP. This allows RGS2 to accelerate G[alpha]^sub i^-GTPase activity, enhance G[alpha][beta]γ^sub i^ trimer formation, and inhibit G[beta]γ^sub i^-dependent PLC-[beta]3 activity.[PUBLICATION ABSTRACT]
Publisher
Springer Nature B.V
Subject
