Muscarinic Stimulation and cGMP Synthesis in the Nervous System

Abstract

Muscarinic agonists have been shown by several investigators to increase tissue levels of cGMP in the nervous system. Thus, ACh, bethanechol and carbachol raise tissue levels of cGMP in slices of sympathetic ganglion and brain, and in N1E 115 neuroblastoma cells. The increase in cGMP level is 5–10, 2 and 20–200 fold in the three systems, respectively. The effect of muscarinic agonists on cGMP is blocked by atropine and requires the presence of calcium in the medium. Use of the calcium ionophore A23187 leads to large increases in cGMP levels. Depolarization by high K⁺ of ganglion and brain slices and of neuroblastoma cells also results in elevated cGMP concentrations. These experiments have usually been carried out in the presence of a PDE inhibitor which blocks degradation of cGMP. Therefore, the increased concentrations of the cyclic nucleotide are probably attributable to stimulation of guanylate cyclase, the cGMP synthesizing enzyme, rather than to a decreased degradation of the nucleotide. Guanylate cyclase is present in all three preparations both in membrane-bound and soluble form, with the latter having 2–20 fold higher specific activity. Attempts to show stimulation of guanylate cyclase by muscarinic agonists in broken cell systems have so far been unsuccessful.