INSULINOTROPIC GLUCAGON-LIKE PEPTIDE-1-MEDIATED ACTIVATION OF NONSELECTIVE CATION CURRENTS IN INSULINOMA CELLS IS MIMICKED BY MAITOTOXIN

Maitotoxin (MTX) activates a Ca2+-dependent non-selective cation curre nt (ICa-NS) in insulinoma cells whose time course is identical to non selective cation currents activated by incretin hormones such as gluca gon-like peptide-1 (GLP-1), which stimulate glucose-dependent insulin secretion by activating cAMP signaling pathways, We investigated the m echanism of activation of ICa-NS in insulinoma cells using specific ph armacological reagents, and these studies further support an identity between MTX- and GLP-1-activated currents, ICa-NS is inhibited by extr acellular application of genistein, econazole, and SKF 96365. This inh ibition by genistein suggests that tyrosine phophorylation may play a role in the activation of ICa-NS. ICa-NS is not inhibited by incubatio n of cells in glucose-free solution, by extracellular tetrodotoxin, ni modipine, or tetraethylammonium, or by intracellular dialysis with 4-a minopyridine, ATP, ryanodine, or heparin, ICa-NS is also not significa ntly inhibited by staurosporine, which does, however, partially inhibi t the MTX-induced rise of intracellular Ca2+ concentration, These effe cts of staurosporine suggest that protein kinase C may not be involved in the activation of ICa-NS but that it may regulate intracellular Ca 2+ release, Alternatively, ICa-NS may have a small component that is c arried through separate divalent cation-selective channels that are in hibited by staurosporine. ICa-NS is neither activated nor inhibited by dialysis with KF, KF + AlF3 or GTP gamma S (guanosine 5'-O-(3-thiotri phosphate)), suggesting that GTP-binding proteins do not play a major role in the activation of this current.