Analysis of presynaptic guanylyl cyclase cascade during adrenergic enhancement of transmitter release

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We have previously reported that norepinephrine (NE) induces a sustained potentiation of transmitter release in the chick ciliary ganglion through a mechanism pharmacologically distinct form any known adrenergic receptors. Here we report that the adrenergic potentiation of transmitter release was enhanced by a phosphodiesterase (PDE) inhibitor, 3-isobutyl-1-methylxanthine (IBMX) and by zaprinast, an inhibitor of cGMP-selective phosphodiesterase. Exogenous application of the membrane-permeable cGMP, 8Br-cGMP, potentiated the quantal transmitter release and, after potentiation, the addition of NE was no longer effective. On the other hand, 8Br-cAMP neither potentiated the transmitter release nor occluded the NE-induced potentiation. The NE-induced potentiation was blocked by neither NO synthase inhibitor nor NO scavenger. The quantal transmitter release was not potentiated by NO donors, e.g. sodium nitroprusside (SNP). The NE-induced potentiation and its enhancement by IBMX was antagonized by two inhibitors of protein kinase G (PKG), Rp-8pCPT-cGMPS and KT5823. As with NE-induced potentiation, the effects of 8Br-cGMP on both the resting [CaィイD12+ィエD1]ィイD2iィエD2 and the action potential-dependent increment of [CaィイD12+ィエD1]ィイD2iィエD2 (ΔCa) in the presynaptic terminal were negligible. The reduction of the paired-pulse ratio of EPSC is consistent with the notion that the NE/cGMP-dependent poteitiation of transmitter release was due mainly to an increase of the exocytotic fusion probability. These results indicate that NE binds to a novel adrenergic receptor that activate guanylyl cyclase and that accumulation of cGMP activates PKG, which may phosphorylate a target protein involved in the exocytosis of synaptic vesicles.