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This Article Full Text Full Text (PDF) All Versions of this Article: 98/6/3397    most recent 00536.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Kang, Y. Articles by Hirai, T. Search for Related Content PubMed PubMed Citation Articles by Kang, Y. Articles by Hirai, T.

Nitric Oxide Activates Leak K⁺ Currents in the Presumed Cholinergic Neuron of Basal Forebrain

¹Departments of Neuroscience and Oral Physiology and ⁴Removable Prosthodontics, Osaka University Graduate School of Dentistry, Suita, Osaka; and ²The Research Institute of Personalized Health Science, ³Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, ⁵Department of Removable Prosthodontics, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido, Japan

Submitted 14 May 2007; accepted in final form 5 October 2007

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 µM Rp-8-bromo-β-phenyl-1,N²-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.

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