title: Postsynaptic NO/cGMP increases NMDA receptor currents via hyperpolarization-activated cyclic nucleotide-gated channels in the hippocampus.
abstract: The nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling cascade participates in the modulation of synaptic transmission. The effects of NO are mediated by the NO-sensitive cGMP-forming guanylyl cyclases (NO-GCs), which exist in 2 isoforms with indistinguishable regulatory properties. The lack of long-term potentiation (LTP) in knock-out (KO) mice deficient in either one of the NO-GC isoforms indicates the contribution of both NO-GCs to LTP. Recently, we showed that the NO-GC1 isoform is located presynaptically in glutamatergic neurons and increases the glutamate release via hyperpolarization-activated cyclic nucleotide (HCN)-gated channels in the hippocampus. Electrophysiological analysis of hippocampal CA1 neurons in whole-cell recordings revealed a reduction of HCN currents and a hyperpolarizing shift of the activation curve in the NO-GC2 KOs associated with reduced resting membrane potentials. These features were mimicked in wild-type (WT) neurons with an NO-GC inhibitor. Analysis of glutamate receptors revealed a cGMP-dependent reduction of NMDA receptor currents in the NO-GC2 KO mice, which was mimicked in WT by HCN channel inhibition. Lowering extracellular Mg(2+) increased NMDA receptor currents in the NO-GC2 KO and allowed the induction of LTP that was absent at physiological Mg(2+). In sum, our data indicate that postsynaptic cGMP increases the N-methyl-D-aspartate (NMDA) receptor current by gating HCN channels and thereby is required for LTP.
authors: Institute of Physiology and Pathophysiology, University Medical Center of the Johannes-Gutenberg University, D-55128 Mainz, Germany and.
authors: Angela
authors: A
authors: Neitz
authors: Department of Pharmacology and Toxicology.
authors: Evanthia
authors: E
authors: Mergia
authors: Institute of Physiology and Pathophysiology, University Medical Center of the Johannes-Gutenberg University, D-55128 Mainz, Germany and.
authors: Barbara
authors: B
authors: Imbrosci
authors: Department of Neuroanatomy and Molecular Brain Research.
authors: Elisabeth
authors: E
authors: Petrasch-Parwez
authors: Department of Experimental Neurophysiology, Ruhr-Universität Bochum, D-44780 Bochum, Germany.
authors: Ulf T
authors: UT
authors: Eysel
authors: Department of Pharmacology and Toxicology.
authors: Doris
authors: D
authors: Koesling
authors: Institute of Physiology and Pathophysiology, University Medical Center of the Johannes-Gutenberg University, D-55128 Mainz, Germany and.
authors: Thomas
authors: T
authors: Mittmann
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D056547:CA1 Region, Hippocampal / Q000166:cytology*; D006152:Cyclic GMP / Q000378:metabolism* / Q000494:pharmacology; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000378:metabolism; D066298:In Vitro Techniques; D008012:Lidocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000172:deficiency* / Q000235:genetics; D018408:Patch-Clamp Techniques; D011743:Pyrimidines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D019789:Tetraethylammonium / Q000494:pharmacology
chemical_list: D000779:Anesthetics, Local; D018691:Excitatory Amino Acid Antagonists; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D011743:Pyrimidines; D016194:Receptors, N-Methyl-D-Aspartate; C082246:ICI D2788; C012647:QX-314; D009569:Nitric Oxide; D019789:Tetraethylammonium; D008012:Lidocaine; D006162:Guanylate Cyclase; D006152:Cyclic GMP
keywords: HCN channels; KO; NMDA receptor; NO; cGMP; guanylyl cyclase; hippocampus