Maitotoxin effects are blocked by SK&F 96365, an inhibitor of receptor-mediated calcium entry.
The dinoflagellate toxin maitotoxin (MTX) elicited a sustained increase of [Ca2+]i in C6 glioma cells. This response was inhibited by SK&F 96365, a blocker of receptor-mediated calcium entry. In C6 cells, endothelin-1 elicited a rapid but transient increase in [Ca2+]i, followed by a smaller sustained increase. SK&F 96365 inhibited the sustained increase in [Ca2+]i. In both C6 glioma cells and RIN insulinoma cells, MTX elicited a marked influx of 45Ca2+. SK&F 96365 inhibited MTX-induced 45Ca2+ influx by 95% at 30 microM. The L-type calcium channel blocker nifedipine, even at 10 microM, inhibited MTX-induced calcium uptake by only 20% in RIN cells and by only 10% in C6 cells. MTX elicited calcium-dependent phosphoinositide breakdown in both C6 and RIN cells. In both cell lines, the MTX-induced phosphoinositide breakdown was inhibited by 90% by SK&F 96365 at 30 microM. Endothelin-1 and carbamylcholine elicited phosphoinositide breakdown in C6 cells and RIN cells, respectively. The stimulations were unaffected by the presence of SK&F 96365 up to 100 microM. In RIN insulinoma cells, MTX elicited calcium-dependent release of insulin. SK&F 96365 at 30 microM inhibited MTX-induced insulin release by 75%, whereas nifedipine, even at 30 microM, inhibited release by only 10%. The blockade of MTX-induced responses by SK&F 96365 indicates that MTX increases intracellular calcium by interacting directly with a calcium-entry system that is similar, in its sensitivity to SK&F 96365, to the calcium-entry system activated by receptors that elicit phosphoinositide breakdown. Activation of phospholipase C and hormone release by MTX also are blocked by SK&F 96365 and, thus, may be secondary to the activation of such a calcium-entry system.
Soergel
D G
DG
Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Yasumoto
T
T
Daly
J W
JW
Gusovsky
F
F
D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology; D005910:Glioma / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D008387:Marine Toxins / Q000037:antagonists & inhibitors*; D009543:Nifedipine / Q000494:pharmacology; D035964:Oxocins; D010716:Phosphatidylinositols / Q000378:metabolism; D011863:Radioimmunoassay; D014407:Tumor Cells, Cultured; D000095702:Polyether Toxins
D002118:Calcium; D002121:Calcium Channel Blockers; D002217:Carbachol; D016232:Endothelins; D007093:Imidazoles; D007328:Insulin; D008387:Marine Toxins; D009543:Nifedipine; D035964:Oxocins; D010716:Phosphatidylinositols; C020394:maitotoxin; D000095702:Polyether Toxins; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole