Differential Mechanisms Underlying the Modulation of Delayed-Rectifier K+ Channel in Mouse Neocortical Neurons by Nitric Oxide

• Published in: Journal of neurophysiology 2006-04, Vol.95 (4), p.2167-2178
• Main Authors: Han, Nian-Lin R, Ye, Jian-Shan, Yu, Albert Cheung Hoi, Sheu, Fwu-Shan
• Format: Article
• Language: English
• Subjects: Animals; Cyclic GMP - antagonists & inhibitors; Cyclic GMP - physiology; Cyclic GMP-Dependent Protein Kinases - metabolism; Delayed Rectifier Potassium Channels - drug effects; Delayed Rectifier Potassium Channels - physiology; Dithiothreitol - pharmacology; Dose-Response Relationship, Drug; Electrophysiology; Mice; Mice, Inbred Strains; Neocortex - drug effects; Neocortex - physiology; Neurons - drug effects; Neurons - physiology; Nitric Oxide - pharmacology; Nitric Oxide - physiology; Nitric Oxide Donors - pharmacology; Oxidation-Reduction; Patch-Clamp Techniques; Potassium - metabolism; S-Nitroso-N-Acetylpenicillamine - pharmacology; Signal Transduction; Superoxides - pharmacology
• ISSN: 0022-3077; 1522-1598
• DOI: 10.1152/jn.01185.2004

1 Department of Biological Sciences, National University of Singapore, Singapore; 2 Neuroscience Research Institute, Peking University and Department of Neurobiology, Peking University Health Science Center, Beijing, China; and 3 The University Scholars Programme, National University of Singapore, Singapore Submitted 17 November 2004; accepted in final form 12 January 2006 The modulatory effects of nitric oxide (NO) on voltage-dependent K + channels are intricate. In our present study, the augmentation and reduction of K + currents by NO donor S -nitro- N -acetylpenicillamine (SNAP) and pure dissolved NO was observed in dissociated neurons from mice neocortex with both whole cell and cell-attached patch clamp. By using a specific electrochemical sensor, the critical concentrations of NO that increased or reduced the channel activities were accurately quantified. Low concentrations of SNAP (20 µM) or NO solution (0.1 µM) enhanced whole cell delayed rectifier K + -current ( I K ) and left the fast inactivating A current ( I A ) unchanged. However, high concentrations of SNAP (100 µM) and NO (0.5 µM) reduced both I K and I A currents. In cell-attached experiments, a significant increase in channel open probability (NP 0 ) was observed when using low concentrations of SNAP or NO. High concentrations of SNAP or NO dramatically decreased NP 0 . The increase in channel activities by low concentrations of SNAP was abolished in the presence of either inhibitors of soluble guaylate cyclase or inhibitors of cGMP-dependent protein kinase G, suggesting a link to the NO-cGMP signaling cascade. The reduction of channel activities by high concentrations of SNAP was reversed by the reducing agent dithiothreitol, implying a redox reaction mechanism. Thus both NO-cGMP signaling and a redox mechanism are involved in the modulation of I K channel activity for neuron excitability. Address for reprint requests and other correspondence: F.-S. Sheu, Dept. of Biological Sciences, National University of Singapore, 14 Science Dr. 4, Singapore 117543, Singapore (E-mail: dbssfs{at}nus.edu.sg )