Involvement of cGMP-dependent protein kinase in adrenergic potentiation of transmitter release from the calyx-type presynaptic terminal.
I have previously reported that norepinephrine (NE) induces a sustained potentiation of transmitter release in the chick ciliary ganglion through a mechanism pharmacologically distinct from any known adrenergic receptors. Here I report that the adrenergic potentiation of transmitter release was enhanced by a phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX) and by zaprinast, an inhibitor of cGMP-selective phosphodiesterase. Exogenous application of the membrane-permeable cGMP, 8-bromo-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 nitric oxide (NO) synthase inhibitor nor NO scavenger. The quantal transmitter release was not potentiated by NO donors, e.g., sodium nitroprusside. The NE-induced potentiation and its enhancement by IBMX was antagonized by two inhibitors of protein kinase G (PKG), Rp isomer of 8-(4-chlorophenylthio) guanosine-3', 5'-cyclic monophosphorothioate and KT5823. As with NE-induced potentiation, the effects of 8Br-cGMP on both the resting intraterminal [Ca2+] ([Ca2+]i) and the action potential-dependent increment of [Ca2+]i (DeltaCa) in the presynaptic terminal were negligible. The reduction of the paired pulse ratio of EPSC is consistent with the notion that the NE- and cGMP-dependent potentiation of transmitter release was attributable mainly to an increase of the exocytotic fusion probability. These results indicate that NE binds to a novel adrenergic receptor that activates guanylyl cyclase and that accumulation of cGMP activates PKG, which may phosphorylate a target protein involved in the exocytosis of synaptic vesicles.
Yawo
H
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Department of Neurophysiology, Tohoku University School of Medicine, Sendai 980-8575, Japan.
D018674:Adrenergic Antagonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002642:Chick Embryo; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005089:Exocytosis / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D005726:Ganglia, Parasympathetic / Q000166:cytology / Q000196:embryology; D066298:In Vitro Techniques; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011941:Receptors, Adrenergic / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013572:Synaptic Vesicles / Q000187:drug effects / Q000502:physiology
D018674:Adrenergic Antagonists; D016166:Free Radical Scavengers; D018377:Neurotransmitter Agents; D020030:Nitric Oxide Donors; D010726:Phosphodiesterase Inhibitors; D011941:Receptors, Adrenergic; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D017869:Cyclic GMP-Dependent Protein Kinases; D011493:Protein Kinase C; D006152:Cyclic GMP; D002118:Calcium; D009638:Norepinephrine