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Am J Physiol Cell Physiol 279: C925-C934, 2000;
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Vol. 279, Issue 4, C925-C934, October 2000

Heterologous desensitization of response mediated by selective PKC-dependent phosphorylation of Gi-1 and Gi-2

K. S. Murthy, J. R. Grider, and G. M. Makhlouf

Departments of Medicine and Physiology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298-0711

This study examined the ability of protein kinase C (PKC) to induce heterologous desensitization by targeting specific G proteins and limiting their ability to transduce signals in smooth muscle. Activation of PKC by pretreatment of intestinal smooth muscle cells with phorbol 12-myristate 13-acetate, cholecystokinin octapeptide, or the phosphatase 1 and phosphatase 2A inhibitor, calyculin A, selectively phosphorylated Galpha i-1 and Galpha i-2, but not Galpha i-3 or Galpha o, and blocked inhibition of adenylyl cyclase mediated by somatostatin receptors coupled to Gi-1 and opioid receptors coupled to Gi-2, but not by muscarinic M2 and adenosine A1 receptors coupled to Gi-3. Phosphorylation of Galpha i-1 and Galpha i-2 and blockade of cyclase inhibition were reversed by calphostin C and bisindolylmaleimide, and additively by selective inhibitors of PKCalpha and PKCvarepsilon . Blockade of inhibition was prevented by downregulation of PKC. Phosphorylation of Galpha -subunits by PKC also affected responses mediated by beta gamma -subunits. Pretreatment of muscle cells with cANP-(4-23), a selective agonist of the natriuretic peptide clearance receptor, NPR-C, which activates phospholipase C (PLC)-beta 3 via the beta gamma -subunits of Gi-1 and Gi-2, inhibited the PLC-beta response to somatostatin and [D-Pen2,5]enkephalin. The inhibition was partly reversed by calphostin C. Short-term activation of PKC had no effect on receptor binding or effector enzyme (adenylyl cyclase or PLC-beta ) activity. We conclude that selective phosphorylation of Galpha i-1 and Galpha i-2 by PKC partly accounts for heterologous desensitization of responses mediated by the alpha - and beta gamma -subunits of both G proteins. The desensitization reflects a decrease in reassociation and thus availability of heterotrimeric G proteins.

G proteins; smooth muscle; signal transduction


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