Alternate coupling of receptors to G(s) and G(i) in pancreatic and submandibular gland cells

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

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

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 Cβ 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 β-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 Gα(s), Gα(i), and phosphatidylinositol 4,5-bisphosphate, pertussis toxin, RGS4, a fragment of β-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 Gα15 -/- 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.

Original languageEnglish (US)
Pages (from-to)17684-17690
Number of pages7
JournalJournal of Biological Chemistry
Volume274
Issue number25
DOIs
StatePublished - Jun 18 1999

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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