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Evidence for Inhibition by Protein Kinase A of Receptor/G_q/Phospholipase C (PLC) Coupling by a Mechanism Not Involving PLC_ß2¹

Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, Texas 77030

Address all correspondence and requests for reprints to: Barbara M. Sanborn, Ph.D., Department of Biochemistry and Molecular Biology, University of Texas Houston Medical School, P.O. Box 20708, Houston, Texas 77225. E-mail: bsanborn{at}utmmg.med.uth.tmc.edu

The effects of cAMP on the oxytocin-stimulated increase in phosphatidylinositide turnover and the possible pathways involved were investigated in a human myometrial cell line (PHM1–41) and in COS-M6 cells overexpressing the oxytocin receptor. Preincubation with chlorophenylthio-cAMP (CPT-cAMP), forskolin, or relaxin inhibited oxytocin-stimulated phosphatidylinositide turnover in PHM1–41 cells, and the inhibition was reversed by H-89, a relatively specific protein kinase A inhibitor. Both CPT-cAMP and transiently expressed protein kinase A catalytic subunit inhibited stimulation by oxytocin and carbachol of [³H]inositol 1,3,4-trisphosphate formation in COS-M6 cells expressing oxytocin or muscarinic M1 receptors, respectively. CPT-cAMP also inhibited phosphatidylinositide turnover stimulation by endothelin-1 in PHM1–41 cells, further demonstrating the generality of the cAMP-inhibitory mechanism. Since Gß activation of phospholipase C_ß2 (PLC_ß2) is a suggested target of protein kinase A, the possibility that the oxytocin receptor couples to PLC_ß2 via G_iGß activation was explored. Western blot analysis of PHM1–41cells and COS-M6 cells detected PLC_ß1 and PLC_ß3, but not PLC_ß2. In PHM1–41 cells, pertussis toxin reduced the oxytocin-stimulated increase in [³H]inositol 1,3,4-trisphosphate by 53%, and this was reversed completely by H-89. Thus, the inhibitory effect of pertussis toxin may result from an indirect effect of cAMP elevation. These data suggest that receptor/G_q-coupled stimulation of PLC_ß1 or PLC_ß3 can be inhibited by cAMP through a phosphorylation mechanism involving protein kinase A that does not involve PLC_ß2. In smooth muscle, this mechanism could constitute potentially important cross-talk between pathways regulating contraction and relaxation.

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