A nitric oxide cyclic GMP-dependent protein kinase pathway alters transmitter release and inhibition by somatostatin at a site downstream of calcium entry

We have examined the somatostatin-mediated modulation of acetylcholine rele ase from intact chick embryo choroid tissue and compared these data with th ose obtained using acutely dissociated neuronal cell bodies from the chick ciliary ganglion, Acetylcholine release, evoked in a calcium-dependent mann er by a high potassium (55 mM KCI) stimulation in both preparations, was in hibited almost completely by 100 nM somatostatin. Measurement of intracellu lar calcium in these neurons revealed that somatostatin blocked the large c alcium transient that was observed in control neurons following KCI exposur e. The modulatory effect of somatostatin on transmitter release was signifi cantly attenuated by pretreatment with pharmacologic agents that selectivel y block cyclic GMP (cGMP)-dependent protein kinase (PKG) or nitric oxide (N O) synthase. It is interesting that this prevention of somatostatin-mediate d acetylcholine release inhibition occurred without reversal of the somatos tatin-mediated block of the KCI-evoked calcium transient. Furthermore, a NO donor or cGMP analogue could block KCI-evoked acetylcholine release, but o nly cGMP could reduce the KCI-evoked calcium transient. Although cGMP could reduce the KCI-evoked calcium transient, a cGMP analogue was shown to redu ce calcium ionophore-evoked transmitter release. Thus, somatostatin reduces acetylcholine release by modulating calcium influx, but the NO-PKG pathway can inhibit acetylcholine release, and alter somatostatin-mediated inhibit ion, by affecting transmitter release at some point after calcium entry.