Dual Pathways in Muscarinic Receptor Stimulation of Phosphoinositide Hydrolysis

The relationships between phosphoinositide hydrolysis induced by various muscarinic agonists and by membrane depolarization agents were investigated in rat cerebral cortex and heart atrium slices. In both preparations, phosphoinositide hydrolysis was stimulated by a combination of carbamylcholine and membrane depolarization with 40 mM K₊ in a synergistic fashion. The synergism was more pronounced at lower external calcium ion concentrations and was sensitive to verapamil. Lower external calcium ion concentrations were required for demonstration of the synergism in heart atrium slices than in cerebral cortex slices. The carbamylcholine-induced stimulation was only partially additive with membrane depolarization via Na₊ channel gating by batrachotoxin. In addition, K₊ depolarization eliminated the sensitivity of carbamylcholine-stimulated phosphoinositide hydrolysis to the sodium channel blocker tetrodotoxin. Our results suggest that muscarinically stimulated phosphoinositide hydrolysis in rat cerebral cortex and heart atrium slices may occur by dual pathways which interact synergistically and that only one of the pathways is depolarization-dependent. Different muscarinic agonists could preferentially utilize these pathways, thus perhaps explaining their different potencies in stimulating phosphoinositide hydrolysis.