Menbrane phospholipase c activation and signal transduction in relation to change of receptor-linkage mechanism

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The mechanism of functional shift from muscarinic to nicotinic cholinergic receptors involved in cytosolic Ca^<++> mobilization and inositol triphosphate (IP_3) during the primary culture of adrenal chromaffin cells was studied. At 0.5 day in culture, muscarine, a specific agonist for muscarinic receptors, caused a greater effect on intracellular Ca^<2+> mobilization and the accumulation of Ins(1,3,4)P_3 than did the nicotinic-specific agonist nicotine. On the contrary, at 5 days, nicotine produced a greater effect on the accumulation of Ins(1,3,4)P_3 and intracellular calcium mobilization than did muscarine. Furthermore, at 0.5 day, the muscarinic antagonist atropine strongly inhibited the increase in InsP_3 accumulation that was induced by the nonspecific agonist carbachol, whereas at 5 days the inhibitory effect of atropine was greatly lowered. On the other hand, the nicotinic receptor antagonists hexamethonium and - tubocurarine showed a much higher inhibitory potency at 5 days compared with 0.5 day in culture. Binding experiments with a muscarinic ligand excluded the possibility that the reduction in muscarinic effects on InsP_3 and intracellular Ca^<2+> mobilization were due to disappearance of the muscarinic receptor itself. These data show that cholinergic receptors linked to the accumulation of InsP_3 and Ca^<2+> mobilization functionally shift from muscarinic to nicotinic during primary culture of adrenal chromaffin cells.