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J Biol Chem, Vol. 274, Issue 25, 17684-17690, June 18, 1999

Alternate Coupling of Receptors to G_s and G_i in Pancreatic and Submandibular Gland Cells

Xiang Luo, Weizhong Zeng, Xin Xu, Serguei Popov^§, Isabelle Davignon^§, Thomas M. Wilkie^§, Susanne M. Mumby^§, and Shmuel Muallem

From the Departments of  Physiology and ^§ Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75235

Many G_s-coupled receptors can activate both cAMP and Ca²⁺ signaling pathways. Three mechanisms for dual activation have been proposed. One is receptor coupling to both G_s and G₁₅ (a G_q class heterotrimeric G protein) to initiate independent signaling cascades that elevate intracellular levels of cAMP and Ca⁺², respectively. The other two mechanisms involve cAMP-dependent protein kinase-mediated activation of phospholipase C either directly or by switching receptor coupling from G_s to G_i. These mechanisms were primarily inferred from studies with transfected cell lines. In native cells we found that two G_s-coupled receptors (the vasoactive intestinal peptide and -adrenergic receptors) in pancreatic acinar and submandibular gland duct cells, respectively, evoke a Ca²⁺ signal by a mechanism involving both G_s and G_i. This inference was based on the inhibitory action of antibodies specific for G_s, G_i, and phosphatidylinositol 4,5-bisphosphate, pertussis toxin, RGS4, a fragment of -adrenergic receptor kinase and inhibitors of cAMP-dependent protein kinase. By contrast, Ca²⁺ signaling evoked by G_s-coupled receptor agonists was not blocked by G_q class-specific antibodies and was unaffected in G₁₅ / knockout mice. We conclude that sequential activation of G_s and G_i, mediated by cAMP-dependent protein kinase, may represent a general mechanism in native cells for dual stimulation of signaling pathways by G_s-coupled receptors.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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