Stimulatory effects of maitotoxin on insulin release in insulinoma HIT cells: role of calcium uptake and phosphoinositide breakdown.
In hamster insulinoma (HIT) cells, maitotoxin (MTX) induces a time-dependent and concentration-dependent release of insulin that requires the presence of extracellular calcium. The response is nearly completely blocked by cinnarizine and cadmium, but is not inhibited by the L-type calcium channel blocker nifedipine or by manganese. MTX induces 45Ca+ uptake in these cells in a dose-dependent mode, and the uptake is blocked with cinnarizine, nifedipine and cadmium, and is partially inhibited by manganese. MTX induces phosphoinositide breakdown in HIT cells, and the response is partially blocked by cadmium, but is not affected by nifedipine, cinnarizine or manganese. High concentrations of potassium ions also induce insulin release and calcium uptake in HIT cells. Both effects of potassium are blocked partially by nifedipine, cadmium and cinnarizine. High concentrations of potassium do not induce phosphoinositide breakdown in HIT cells. The results suggest that MTX-elicited release of insulin is attained by two mechanisms: 1) a nifedipine-sensitive action, which results from MTX-induced activation of L-type calcium channels, which can be mimicked with high potassium concentrations; and 2) a nifedipine-insensitive action, which may be initiated by the activation of phosphoinositide breakdown by MTX. Such an activation of phospholipase C would result in the formation of 1,4,5-inositol trisphosphate, a release of intracellular calcium and then release of insulin to the extracellular space. Cinnarizine is proposed to block both MTX-elicited mechanisms, the first by blockade of calcium channels and the second by blocking 1,4,5-inositol trisphosphate-induced release of internal calcium. Either mechanism alone appears capable of eliciting release of insulin.
Soergel
D G
DG
Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, maryland.
Gusovsky
F
F
Yasumoto
T
T
Daly
J W
JW
D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000493:pharmacokinetics; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002132:Calcium Radioisotopes; D002936:Cinnarizine / Q000494:pharmacology; D006224:Cricetinae; D006168:Guinea Pigs; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma / Q000378:metabolism* / Q000473:pathology; D008345:Manganese / Q000494:pharmacology; D008387:Marine Toxins / Q000494:pharmacology*; D009543:Nifedipine / Q000494:pharmacology; D035964:Oxocins; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010716:Phosphatidylinositols / Q000378:metabolism; D013552:Swine; D014407:Tumor Cells, Cultured; D000095702:Polyether Toxins
D002104:Cadmium; D002118:Calcium; D002121:Calcium Channel Blockers; D002132:Calcium Radioisotopes; D002936:Cinnarizine; D007328:Insulin; D008345:Manganese; D008387:Marine Toxins; D009543:Nifedipine; D035964:Oxocins; D010716:Phosphatidylinositols; C020394:maitotoxin; D000095702:Polyether Toxins