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dc.titleGlucose activates the carboxyl methylation of subunits of trimeric GTP- binding proteins in pancreatic β cells: Modulation in vivo by calcium, GTP, and pertussis toxin
dc.contributor.authorKowluru, A.
dc.contributor.authorLi, G.
dc.contributor.authorMetz, S.A.
dc.identifier.citationKowluru, A.,Li, G.,Metz, S.A. (1997-09-15). Glucose activates the carboxyl methylation of subunits of trimeric GTP- binding proteins in pancreatic β cells: Modulation in vivo by calcium, GTP, and pertussis toxin. Journal of Clinical Investigation 100 (6) : 1596-1610. ScholarBank@NUS Repository.
dc.description.abstractThe γ subunits of trimeric G-proteins (γ1, γ2, γ5, and γ7 isoforms) were found to be methylated at their carboxyl termini in normal rat islets, human islets and pure β [HIT-T15] cells. Of these, GTPγS significantly stimulated the carboxyl methylation selectively of γ2 and γ5 isoforms. Exposure of intact HIT cells to either of two receptor- independent agonists-a stimulatory concentration of glucose or a depolarizing concentration of K+-resulted in a rapid (within 30 s) and sustained (at least up to 60 min) stimulation of γ subunit carboxyl methylation. Mastoparan, which directly activates G-proteins (and insulin secretion from β cells), also stimulated the carboxyl methylation of γ subunits in intact HIT cells. Stimulatory effects of glucose or K+ were not demonstrable after removal of extracellular Ca2+ or depletion of intracellular GTP, implying regulatory roles for calcium fluxes and GTP; however, the methyl transferase itself was not directly activated by either. The stimulatory effects of mastoparan were resistant to removal of extracellular Ca2+, implying a mechanism of action that is different from glucose or K+ but also suggesting that dissociation of the αβγ trimer is conducive to γ subunit carboxyl methylation. Indeed, pertussis toxin also markedly attenuated the stimulatory effects of glucose, K+ or mastoparan without altering the rise in intracellular calcium induced by glucose or K+. Glucose-induced carboxyl methylation of γ2 and γ5 isoforms was vitiated by coprovision of any of three structurally different cyclooxygenase inhibitors. Conversely, exogenous PGE2, which activates G(i) and G(o) in HIT cells and which thereby would dissociate α from β(γ), stimulated the carboxyl methylation of γ2 and γ5 isoforms and reversed the inhibition of glucose-stimulated carboxyl methylation of subunits elicited by cyclooxygenase inhibitors. These data indicate that γ subunits of trimeric G-proteins undergo a glucose- and calcium-regulated methylation-demethylation cycle in insulin-secreting cells, findings that may imply an important role in β cell function. Furthermore, this is the first example of the regulation of the posttranslational modification of G-protein γ subunits via nonreceptor-mediated activation mechanisms, which are apparently dependent on calcium influx and the consequent activation of phospholipases releasing arachidonic acid.
dc.subjectCyclooxygenase inhibitors and insulin secretion
dc.subjectGTP-binding proteins
dc.subjectPancreatic β cells
dc.subjectProstaglandin E2
dc.subjectSubunit carboxyl methylation
dc.description.sourcetitleJournal of Clinical Investigation
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