Effects of maitotoxin on atrial natriuretic factor-mediated accumulation of cyclic GMP in PC12 cells.
Maitotoxin (MTX) activates calcium channels and stimulates phosphoinositide breakdown in pheochromocytoma PC12 cells, while having no effect on basal levels of the cyclic nucleotides cAMP and cGMP. Atrial natriuretic factor (ANF) induces a dose-dependent accumulation of cGMP in PC12 cells through the activation of a membrane bound guanylate cyclase. Effects of ANF on cGMP are independent of extracellular concentrations of calcium. Since agents that activate phosphoinositide breakdown can indirectly affect cyclic nucleotide formation, the effects of MTX on ANF-mediated accumulation of cGMP was studied. MTX induces a dose-dependent inhibition of ANF-mediated accumulation of cGMP. The inhibition by MTX requires the presence of extracellular calcium, but is unaffected by the calcium channel blocker nifedipine. The inhibitory effect of MTX is not mimicked by the calcium ionophore ionomycin. A phorbol ester, PMA, which stimulates protein kinase C, also inhibits ANF-mediated accumulation of cGMP. Sodium nitroprusside induces large accumulations of cGMP in PC12 cells through the stimulation of a soluble guanylate cyclase. Neither MTX nor PMA inhibit nitroprusside-mediated accumulation of cGMP. The results indicate that in PC12 cells, protein kinase C activation, either directly with PMA, and indirectly with MTX through phosphoinositide breakdown and formation of diacylglycerol, leads to inhibition of ANF-mediated, but not nitroprusside-mediated accumulation of cGMP.
Schulick
A
A
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
D009320:Atrial Natriuretic Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D015759:Ionomycin / Q000494:pharmacology; D008387:Marine Toxins / Q000494:pharmacology*; D009543:Nifedipine / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D035964:Oxocins; D010673:Pheochromocytoma; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000095702:Polyether Toxins
D009320:Atrial Natriuretic Factor; D002118:Calcium; D006152:Cyclic GMP; D015759:Ionomycin; D008387:Marine Toxins; D009543:Nifedipine; D009599:Nitroprusside; D035964:Oxocins; D013755:Tetradecanoylphorbol Acetate; C020394:maitotoxin; D000095702:Polyether Toxins