Regulation of cyclic AMP metabolism by muscarinic cholinergic receptors

The occurrence of muscarinic cholinergic receptor-mediated activation of phosphodiesterase in 1321N1 cells does not represent an isolated phenomenon, since a similar response to cholinergic stimuli is observed in thyroid slices (45) and WI-38 fibroblasts (1,42). Both muscarinic-receptor-mediated inhibition of adenylate cyclase and activation of phosphodiesterase occur in WI-38 fibroblasts (42). Work currently under way in our laboratory is directed toward determining if a guanine nucleotide regulatory protein is involved in the activation of phosphodiesterase in these cells and whether common or separate populations of muscarinic receptors are coupled to these two mechanisms of cyclic AMP metabolism. The analysis of acute hormonal regulation of phosphodiesterase in intact cells is sufficiently complicated to have previously discouraged investigators from pursuing this question in mammalian tissues. The 1321N1 cell line provides a simple model system in which at least one mechanism of hormonal regulation of phosphodiesterase can be examined. In light of the widespread occurrence of muscarinic-receptor-mediated effects on Ca2+ mobilization, it would not be surprising to find that this mechanism represents an important part of cholinergic action in both the peripheral and central nervous systems. Indeed, this system could provide an important regulatory link between Ca2+ -mediated and cyclic-AMP-mediated events in target cells. The potential importance of such a mechanism also need not be restricted to the muscarinic receptor system, since any neurotransmitter or hormone receptor system coupled to events involved in Ca2+ mobilization might produce phenomena similar to that observed for muscarinic receptors in 1321N1 cells. Our studies emphasize that two mechanisms for regulation of cyclic AMP accumulation by muscarinic cholinergic receptors exist. The data to date suggest that separate receptor subtypes are involved in these mechanisms of cholinergic regulation and provide another biochemical basis whereby the well-known interaction of Ca2+ with the cyclic AMP system can be effected. Thus, identification of the molecular events involved in the regulation of PI turnover and its consequences may be crucial in defining the basis of this aspect of cholinergic action. In addition, more extensive analyses of the phosphodiesterase system using cell-free preparations have the potential of providing clues to the molecular basis of this mechanism.(ABSTRACT TRUNCATED AT 400 WORDS)