MAITOTOXIN EFFECTS ARE BLOCKED BY SK-AND-F-96365, AN INHIBITOR OF RECEPTOR-MEDIATED CALCIUM ENTRY

The dinoflagellate toxin maitotoxin (MTX) elicited a sustained increas e of [Ca2+]i in C6 glioma cells. This response was inhibited by SK&F 9 6365, a blocker of receptor-mediated calcium entry. In C6 cells, endot helin-1 elicited a rapid but transient increase in [Ca2+]i, followed b y a smaller sustained increase. SK&F 96365 inhibited the sustained inc rease in [Ca2+]i. In both C6 glioma cells and RIN insulinoma cells, MT X elicited a marked influx of Ca-45(2+). SK&F 96365 inhibited MTX-indu ced Ca-45(2+) influx by 95% at 30-mu-M. The L-type calcium channel blo cker nifedipine, even at 10-mu-M, inhibited MTX-induced calcium uptake by only 20% in RIN cells and by only 10% in C6 cells. MTX elicited ca lcium-dependent phosphoinositide breakdown in both C6 and RIN cells. I n both cell lines, the MTX-induced phosphoinositide breakdown was inhi bited by 90% by SK&F 96365 at 30-mu-M. Endothelin-1 and carbamylcholin e elicited phosphoinositide breakdown in C6 cells and RIN cells, respe ctively. The stimulations were unaffected by the presence of SK&F 9636 5 up to 100-mu-M. In RIN insulinoma cells, MTX elicited calcium-depend ent release of insulin. SK&F 96365 at 30-mu-M inhibited MTX-induced in sulin release by 75%, whereas nifedipine, even at 30-mu-M, inhibited r elease by only 10%. The blockade of MTX-induced responses by SK&F 9636 5 indicates that MTX increases intracellular calcium by interacting di rectly with a calcium-entry system that is similar, in its sensitivity to SK&F 96365, to the calcium-entry system activated by receptors tha t 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.