Histamine H2 receptor activates adenylate cyclase and PLC via separate GTP-dependent pathways.
Previously, we demonstrated that a single histamine H2 receptor can couple to both the adenosine 3',5'-cyclic monophosphate and inositol 1,4,5-trisphosphate/intracellular Ca2+ signaling pathways in a stimulatory manner. We undertook the present studies to fur her characterize the postreceptor events involved in H2 receptor dual signaling. Histamine H2 receptor-mediated signal transduction was examined in isolated cell membranes prepared from purified canine parietal cells and HEPA cells (rat hepatoma cell line) stably transfected to express the canine H2 histamine receptor cDNA. Histamine dose-dependently stimulated both adenylate cyclase [AC; mean effective concentration (EC50) = 2 x 10(-7) M] and phospholipase C (PLC; EC50 = 3.1 +/- 0.5 x 10(-7) M) activity in an H2-specific and GTP-dependent manner. Cholera toxin pretreatment abolished the stimulatory effect of histamine on PLC activity in isolated membranes without altering binding of the H2 receptor antagonist tiotidine. Anti-Gs alpha dose-dependently inhibited histamine-stimulated AC activity while leaving the effect of this secretagogue on PLC activity unaltered. Although anti-Gq alpha inhibited vasopressin-stimulated PLC activity in HEPA cells and carbachol-stimulated PLC in parietal cells, this antibody did not alter the action of histamine on PLC in the same membrane preparations. Antibody against the NH2 and COOH terminals of the common beta-subunit of heterotrimeric G proteins did not inhibit histamine-stimulated PLC activity. Our studies demonstrate for the the first time that activation of the H2 receptor leads to stimulation of both AC and PLC via separate GTP-dependent mechanisms.
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109-0682, USA.
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Gantz
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DelValle
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000502:physiology; D004285:Dogs; D004789:Enzyme Activation; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology*; D005753:Gastric Mucosa / Q000166:cytology / Q000502:physiology*; D011970:Receptors, Histamine H2 / Q000502:physiology*; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism
D011970:Receptors, Histamine H2; D010738:Type C Phospholipases; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases; D006152:Cyclic GMP