title: Effects of guanine nucleotides on bombesin-stimulated signal transduction in rat pancreatic acinar cells.
abstract: To study the role of guanine nucleotide binding proteins (G proteins) in bombesin receptor signal transduction, we investigated the effects of guanine nucleotide analogues and of the G protein activator NaF on bombesin-induced amylase release, inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) production and release of intracellular Ca2+ in rat pancreatic acini. In digitonin-permeabilized acini, guanosine 5'-[gamma-thio]triphosphate (GTP gamma S), a well-known activator of G proteins, potentiated bombesin-induced Ins(1,4,5)P3 production and increased amylase release at low bombesin concentrations (< 10 nM). By contrast, GTP gamma S decreased bombesin-stimulated amylase release at high bombesin concentrations (> 10 nM). Fluoride (10 mM), another G protein activator, had similar effects to GTP gamma S on amylase release. However, unlike GTP gamma S it had no effect on Ins(1,4,5)P3 production and release of intracellular Ca2+ induced by high bombesin concentrations. GDP and its analogues, such as 2'-desoxyguanosine 5'-diphosphate (dGDP) or guanosine 5'-[beta-thio]diphosphate (GDP beta S), inhibit activation of G proteins. GDP and dGDP both inhibited amylase release and Ins(1,4,5)P3 production at all bombesin concentrations tested. In contrast, GDP beta S mimicked the effects of GTP gamma S on bombesin-stimulated amylase release and Ins(1,4,5)P3 accumulation. In conclusion, we suggest that bombesin receptor-mediated signal transduction involves G proteins in pancreatic acini. The correlation between inhibition of maximum-stimulated enzyme secretion and further increase in Ins(1,4,5)P3 production in response to GTP gamma S at high bombesin concentrations suggests that overstimulation of phospholipase C inhibits amylase release. The discrepant effects of GDP and of GDP beta S on phospholipase C activity and amylase release might be due to the ability of GDP beta S, but not of GDP to activate G proteins persistently after phosphorylation by G protein-associated GDP kinases.
authors.affiliation: Abteilung für Gastroenterologie, Universitätsklinikum, Frankfurt/Main, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Piiper
authors.forename: D
authors.initials: D
authors.lastname: Stryjek-Kaminska
authors.forename: J
authors.initials: J
authors.lastname: Stein
authors.forename: W F
authors.initials: WF
authors.lastname: Caspary
authors.forename: S
authors.initials: S
authors.lastname: Zeuzem
mesh_terms: D000681:Amylases / Q000378:metabolism; D000818:Animals; D001839:Bombesin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002463:Cell Membrane Permeability; D016257:Fura-2 / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006150:Guanine Nucleotides / Q000494:pharmacology*; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D010179:Pancreas / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D018004:Receptors, Bombesin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012969:Sodium Fluoride / Q000494:pharmacology
chemical_list: D006150:Guanine Nucleotides; D018004:Receptors, Bombesin; D015544:Inositol 1,4,5-Trisphosphate; D012969:Sodium Fluoride; D000681:Amylases; D019204:GTP-Binding Proteins; D001839:Bombesin; D002118:Calcium; D016257:Fura-2