title: Nitric oxide activates leak K+ currents in the presumed cholinergic neuron of basal forebrain.
abstract: Learning and memory are critically dependent on basal forebrain cholinergic (BFC) neuron excitability, which is modulated profoundly by leak K(+) channels. Many neuromodulators closing leak K(+) channels have been reported, whereas their endogenous opener remained unknown. We here demonstrate that nitric oxide (NO) can be the endogenous opener of leak K(+) channels in the presumed BFC neurons. Bath application of 1 mM S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, induced a long-lasting hyperpolarization, which was often interrupted by a transient depolarization. Soluble guanylyl cyclase inhibitors prevented SNAP from inducing hyperpolarization but allowed SNAP to cause depolarization, whereas bath application of 0.2 mM 8-bromoguanosine-3',5'-cyclomonophosphate (8-Br-cGMP) induced a similar long-lasting hyperpolarization alone. These observations indicate that the SNAP-induced hyperpolarization and depolarization are mediated by the cGMP-dependent and -independent processes, respectively. When examined with the ramp command pulse applied at -70 mV under the voltage-clamp condition, 8-Br-cGMP application induced the outward current that reversed at K(+) equilibrium potential (E(K)) and displayed Goldman-Hodgkin-Katz rectification, indicating the involvement of voltage-independent K(+) current. By contrast, SNAP application in the presumed BFC neurons either dialyzed with the GTP-free internal solution or in the presence of 10 muM Rp-8-bromo-beta-phenyl-1,N(2)-ethenoguanosine 3',5'-cyclic monophosphorothioate sodium salt, a protein kinase G (PKG) inhibitor, induced the inward current that reversed at potentials much more negative than E(K) and close to the reversal potential of Na(+)-K(+) pump current. These observations strongly suggest that NO activates leak K(+) channels through cGMP-PKG-dependent pathway to markedly decrease the excitability in BFC neurons, while NO simultaneously causes depolarization by the inhibition of Na(+)-K(+) pump through ATP depletion.
authors.affiliation: Department of Neuroscience and Oral Physiology, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan. kang@dent.osaka-u.ac.jp
authors.forename: Youngnam
authors.initials: Y
authors.lastname: Kang
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Dempo
authors.forename: Atsuko
authors.initials: A
authors.lastname: Ohashi
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Saito
authors.forename: Hiroki
authors.initials: H
authors.lastname: Toyoda
authors.forename: Hajime
authors.initials: H
authors.lastname: Sato
authors.forename: Hisashi
authors.initials: H
authors.lastname: Koshino
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Maeda
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Hirai
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D001464:Barium / Q000494:pharmacology; D002586:Cesium / Q000494:pharmacology; D006152:Cyclic GMP / Q000502:physiology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D003627:Data Interpretation, Statistical; D004594:Electrophysiology; D005260:Female; D005456:Fluorescent Dyes; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000145:classification / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010275:Parasympathetic Nervous System / Q000166:cytology / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects*; D016548:Prosencephalon / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors
chemical_list: D005456:Fluorescent Dyes; D020030:Nitric Oxide Donors; D015221:Potassium Channels; D002586:Cesium; D001464:Barium; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D000255:Adenosine Triphosphate; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D000254:Sodium-Potassium-Exchanging ATPase; D006152:Cyclic GMP