Dihydropyridine calcium channel activators and antagonists influence depolarization-evoked inositol phospholipid hydrolysis in brain

Abstract

Increased inositol phospholipid hydrolysis induced by elevated extracellular K+ was directly monitored by assaying [3H]inositol phosphate accumulation following prelabelling of cerebral cortical slices with [3H]inositol. Depolarization evoked by K+ increased [3H]inositol phosphate accumulation with a 2-3-fold stimulation observed at 18 mM K+. Higher concentrations of K+ failed to further increase accumulation though a suppression of the incorporation of [3H]inositol into phospholipid at higher K+ could complicate these results. Slices incubated with the dihydropyridine calcium channel activator BAY-K-8644 resulted in a much increased response to 12 mM and 18 mM K+ with substantially smaller enhancement of basal (6 mM) or much higher (30 and 55 mM) K+. The [3H]inositol phosphate response induced by 18 mM K+ + 1 microM BAY-K-8644 was markedly reduced when incubations were performed in the presence of reduced Ca2+. Similarly, preincubation of slices with the dihydropyridine antagonist PN-200-110 suppressed the response to K+ and to K+ + BAY-K-8644. This effect was stereospecific with the (+)-enantiomer being at least 100-fold more potent than the (-)-enantiomer. These data provide primary evidence for functional dihydropyridine-sensitive calcium channels in brain.