McHardy Smith - Regulation of cyclic AMP metabolism by muscarinic cholinergic receptors.

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  Harden, T. K., Evans, T., Hepler, J. R., Hughes, A. R., Martin,   M. W., Meeker, R. B., Smith, M. M., Tanner, L. I. 19  207-20-

  Abstract: 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)

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