Phosphoinositide hydrolysis induced by depolarization and sodium channel activation in mouse cerebrocortical slices.

Carbachol, a muscarinic receptor agonist and the sodium channel-activating agents, scorpion venom, veratridine, batrachotoxin and aconitine, were shown to stimulate the formation of [3H]inositol phosphates in [3H]inositol-labelled miniprisms, obtained from the cerebral cortex of the mouse. The inositol response to the Na+ channel-activating agents was inhibited by the sodium channel blocker tetrodotoxin (TTX), while the response induced by carbachol was partially resistant to TTX. The response to scorpion venom and the TTX-insensitive portion of the response to carbachol was additive, indicating different mechanisms. The presence of high potassium (K+) induced hydrolysis of inositide in a TTX-insensitive manner and was not additive with that resulting from sodium channel activators, thus indicating a common mechanism. The addition of large concentrations of magnesium to block the release of acetylcholine, did not inhibit the inositol response to high K+ or to veratridine. Calcium channel blockers such as nickel or cobalt, or the dihydropyridine calcium (Ca2+) channel activator BAY K 8644 and the calcium channel blocker nifedipine, nimodipine or PN-200 110 had little effect. Monensin, a sodium ionophore, stimulated the turnover of phosphatidylinositol at non-depolarizing concentrations and the omission of Na+ ions inhibited the response to sodium channel agents and to high K+. Thus, membrane potential and gradients of K+, Na+ and Ca2+ are all important factors determining the final effect on the turnover of phosphatidylinositol. The data are consistent with a model in which all these factors impinge on the Na+/Ca2+ exchanger regulating internal Ca2+ that, in turn, activates phospholipase C.