Ca. Leech et Jf. Habener, INSULINOTROPIC GLUCAGON-LIKE PEPTIDE-1-MEDIATED ACTIVATION OF NONSELECTIVE CATION CURRENTS IN INSULINOMA CELLS IS MIMICKED BY MAITOTOXIN, The Journal of biological chemistry, 272(29), 1997, pp. 17987-17993
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.