Relationship between the partial inhibition of muscarinic receptor-mediated phosphoinositide hydrolysis by phorbol esters and tetrodotoxin in rat cerebral cortex

Our results demonstrate that phorbol esters and tetrodotoxin (TTX) partially inhibit muscarinic receptor-mediated increase in phosphoinositide (PI) hydrolysis in rat cerebral cortex cell aggregates; this inhibition was observed using several muscarinic agonists. While these effects were not accompanied by major changes in the total muscarinic receptor population, phorbol esters, but not TTX, reduced the relative concentration of the high affinity binding sites of the M₁-selective ligands pirenzepine and telenzepine. In contrast, the binding of a muscarinic agonist to multiple receptor conformations was not influenced by either phorbol esters or TTX. Our data also show that the partial inhibition of the PI response by these agents is not due to a selective effect on the response mediated by a certain muscarinic receptor subtype or a receptor population which is more sensitive to agonist-induced desensitization. Evidence is provided that the effects of both phorbol esters and TTX might be mediated largely, although not entirely, by a common mechanism.