Insulinotropic Glucagon-like Peptide-1-mediated Activation of Non-selective Cation Currents in Insulinoma Cells Is Mimicked by Maitotoxin

• Published in: The Journal of biological chemistry Vol. 272; no. 29; pp. 17987 - 17993
• Main Authors: Leech, Colin A., Habener, Joel F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.07.1997; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Calcium - metabolism; Calcium - pharmacology; Calcium Channel Blockers - pharmacology; Calcium Channels - drug effects; Calcium Channels - physiology; Cricetinae; Egtazic Acid - pharmacology; Glucagon-Like Peptide 1; Imidazoles - pharmacology; Insulinoma; Islets of Langerhans; Marine Toxins - pharmacology; Membrane Potentials - drug effects; Oxocins; Pancreatic Neoplasms; Peptides - pharmacology; Staurosporine - pharmacology; Tumor Cells, Cultured
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.272.29.17987

Maitotoxin (MTX) activates a Ca2+-dependent non-selective cation current (ICa-NS) in insulinoma cells whose time course is identical to non-selective cation currents activated by incretin hormones such as glucagon-like peptide-1 (GLP-1), which stimulate glucose-dependent insulin secretion by activating cAMP signaling pathways. We investigated the mechanism of activation of ICa-NS in insulinoma cells using specific pharmacological reagents, and these studies further support an identity between MTX- and GLP-1-activated currents. ICa-NS is inhibited by extracellular application of genistein, econazole, and SKF 96365. This inhibition by genistein suggests that tyrosine phophorylation may play a role in the activation of ICa-NS. ICa-NS is not inhibited by incubation of cells in glucose-free solution, by extracellular tetrodotoxin, nimodipine, or tetraethylammonium, or by intracellular dialysis with 4-aminopyridine, ATP, ryanodine, or heparin. ICa-NS is also not significantly inhibited by staurosporine, which does, however, partially inhibit the MTX-induced rise of intracellular Ca2+ concentration. These effects of staurosporine suggest that protein kinase C may not be involved in the activation of ICa-NS but that it may regulate intracellular Ca2+ release. Alternatively, ICa-NS may have a small component that is carried through separate divalent cation-selective channels that are inhibited by staurosporine. ICa-NS is neither activated nor inhibited by dialysis with KF, KF + AlF3 or GTPγS (guanosine 5′-O-(3-thiotriphosphate)), suggesting that GTP-binding proteins do not play a major role in the activation of this current.