Effect of maitotoxin analogues on calcium influx and phosphoinositide breakdown in cultured cells.
Maitotoxin (MTX) and the analogues, bis-desulfated-MTX (didesulfo-MTX), mono-desulfated-MTX (monodesulfo-MTX), and hydrogenated-MTX (H-MTX) were examined on 45Ca2+ influx and phosphoinositide breakdown with hamster insulinoma HIT cells and rat glioma C6 cells. The activity of MTX was greatly reduced either by desulfation or by hydrogenation. Didesulfo-MTX weakly stimulated calcium influx in HIT cells, but had no stimulatory effect on either calcium influx or phosphoinositide breakdown in C6 cells. All the analogues inhibited MTX-induced calcium influx in either HIT or C6 cells. Didesulfo-MTX inhibited the calcium influx elicited by 3 ng/ml MTX in C6 cells with an IC50 of 7.0 +/- 0.7 ng/ml. The data suggest that the sulfate groups in MTX are important for stimulation of calcium influx and phosphoinositide breakdown, but are not essential for binding to a receptor-site on cell membranes. Although catalytic reduction of double bonds in MTX reduced activity by nearly 100-fold, a tritiated H-MTX still represents a potential radioligand for identification of MTX-binding sites.
Murata
M
M
Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, MD 20892.
Gusovsky
F
F
Sasaki
M
M
Yokoyama
A
A
Yasumoto
T
T
Daly
J W
JW
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006224:Cricetinae; D007928:Lethal Dose 50; D008387:Marine Toxins / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D035964:Oxocins; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D000095702:Polyether Toxins
D002118:Calcium; D008387:Marine Toxins; D035964:Oxocins; D010716:Phosphatidylinositols; C020394:maitotoxin; D000095702:Polyether Toxins