Tumor promoter phorbol 12-myristate, 13-acetate inhibits phosphoinositide hydrolysis and cytosolic Ca2+ rise induced by the activation of muscarinic receptors in PC12 cells.

Preincubation of PC12 cells (used both before and after differentiation by NGF) with phorbol myristate acetate (PMA) was without effect on the basal concentration of inositol phosphates (metabolites of phosphoinositide hydrolysis) and of free cytosolic Ca2+, but inhibited considerably the increases induced by the cholinergic agonist carbachol via the activation of the muscarinic receptor. Inasmuch as binding was unaffected, this inhibition might occur at the level of receptor coupling to its transduction mechanism(s). Inhibition appeared within 1 min and was maximal after 3 min. The concentrations of PMA needed (10(-9)-10(-8)M) were in the range believed to cause specifically the activation of protein kinase C. The muscarinic receptor, via the hydrolysis of phosphoinositides and the generation of diacylglycerol, participates in the regulation of the latter enzyme. Our data suggest therefore that the receptor operates under stringent feedback control by the metabolites generated as a consequence of its activation.