LITHIUM STIMULATION OF RAT PANCREATIC BETA-CELL REPLICATION IS MEDIATED THROUGH PERTUSSIS-TOXIN-SENSITIVE GTP-BINDING PROTEINS AND OCCURS INDEPENDENTLY OF CA2-KINASE-C ACTIVATION( INFLUX, CAMP, OR PROTEIN)

We recently demonstrated the mitogenic and secretagogic actions of lit hium in the insulin-producing pancreatic beta-cell (Sjoholm Angstrom, Welsh N, Hellerstrom C: Lithium increases DNA replication, polyamine c ontent and insulin secretion by rat pancreatic beta-cells in vitro, Am J Physiol 262:C391-C395, 1992), In this study, the influence of lithi um on beta-cell signal transduction pathways was monitored and their i mportance for the stimulated cell replication and hormone secretion wa s elucidated by selective pharmacological probes, To this end, fetal r at pancreatic islets enriched in beta-cells were isolated and cultured for 3 days with or without 10 mmol/l LiCl, This resulted in a marked mitogenic response by the beta-cells, of similar magnitude to that obt ained by pharmacological activation of cAMP-dependent protein kinases by forskolin or the Sp-diastereomer of cAMP or protein kinase C stimul ation by phorbol ester, However, neither did Lithium affect the islet content of cAMP (whereas forskolin did), nor was the mitogenic respons e to the ion impeded when islets were pretreated with the Rp-diastereo mer of cAMP, a specific antagonist of cAMP-dependent protein kinases, or by the Ca2+ channel blocker D-BOO, The protein kinase C inhibitor 1 -(5'-isoquinolinesulfonyl)-2-methylpiperazine prevented the mitogenici ty of phorbol ester, but not that of lithium, Conversely, addition of increasing concentrations of inositol along with lithium also did not affect the mitogenicity of the ion, providing indirect evidence agains t the involvement of protein kinase C in mediating the growth-promotin g effect of lithium in this system, It was found that pretreatment of islets with pertussis toxin, which inactivates GTP-binding proteins by ADP-ribosylation, prevented the mitogenicity and part of the secretag ogic action of Lithium, It is concluded that although specific activat ion of the cAMP and protein kinase C signaling systems appears suffici ent to trigger a mitogenic response of the beta-cell, lithium seemingl y does not work through any of these systems nor via Ca2+ influx in pr omoting beta-cell mitogenesis, Our results, moreover, suggest that the actions of Lithium are conveyed by pertussis toxin-sensitive GTP-bind ing proteins.