title: Presynaptic nitric oxide/cGMP facilitates glutamate release via hyperpolarization-activated cyclic nucleotide-gated channels in the hippocampus.
abstract: In hippocampal neurons, synaptic transmission is affected by a variety of modulators, including nitric oxide (NO), which was proposed as a retrograde messenger as long as two decades ago. NO signals via two NO-sensitive guanylyl cyclases (NO-GCs) (NO-GC1 and NO-GC2) and the subsequent increase in cGMP. Lack of long-term potentiation in mice deficient in either one of the two NO-GCs demonstrates the involvement of both NO-GCs in synaptic transmission. However, the physiological consequences of NO/cGMP and the cellular mechanisms involved are unknown. Here, we analyzed glutamatergic synaptic transmission, most likely reflecting glutamate release, in the hippocampal CA1 region of NO-GC knockout mice by single-cell recording, and found glutamate release to be reduced under basal and stimulated conditions in the NO-GC1 knockout mice, but restorable to wild-type-like levels with a cGMP analog. Conversely, an inhibitor of NO/cGMP signaling, ODQ, reduced glutamate release in wild-type mice to knockout-like levels; thus, we conclude that presynaptic cGMP formed by NO-GC1 facilitates glutamate release. In this pathway, NO is supplied by endothelial NO synthase. In search of a cGMP target, we found that two mechanistically distinct blockers of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (ZD7288 and DK-AH269) abolished the cGMP-induced increase in glutamate release, suggesting that cGMP either directly or indirectly signals via HCN channels. In summary, we unravel a presynaptic role of NO/cGMP most likely in glutamate release and propose that HCN channels act as effectors for cGMP.
authors.affiliation: Department of Neurophysiology, Medical School, Ruhr-University Bochum, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Neitz
authors.forename: Evanthia
authors.initials: E
authors.lastname: Mergia
authors.forename: Ulf T
authors.initials: UT
authors.lastname: Eysel
authors.forename: Doris
authors.initials: D
authors.lastname: Koesling
authors.forename: Thomas
authors.initials: T
authors.lastname: Mittmann
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000378:metabolism; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000071756:Soluble Guanylyl Cyclase; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D001552:Benzazepines; D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D020033:Protein Isoforms; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; C082246:ICI D2788; C087873:DK-AH 268; D009569:Nitric Oxide; D018698:Glutamic Acid; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP