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  • Title: Effects of guanine nucleotides on bombesin-stimulated signal transduction in rat pancreatic acinar cells.
    Author: Piiper A, Stryjek-Kaminska D, Stein J, Caspary WF, Zeuzem S.
    Journal: Res Exp Med (Berl); 1993; 193(5):323-35. PubMed ID: 7506443.
    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.
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