Differential mechanisms underlying the modulation of delayed-rectifier K+ channel in mouse neocortical neurons by nitric oxide.
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 microM) or NO solution (0.1 microM) enhanced whole cell delayed rectifier K+ -current (IK) and left the fast inactivating A current (IA) unchanged. However, high concentrations of SNAP (100 microM) and NO (0.5 microM) reduced both IK and IA currents. In cell-attached experiments, a significant increase in channel open probability (NP0) was observed when using low concentrations of SNAP or NO. High concentrations of SNAP or NO dramatically decreased NP0. 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 IK channel activity for neuron excitability.
Han
Nian-Lin R
NL
Department of Biological Sciences, National University of Singapore, Singapore.
Ye
Jian-Shan
JS
Yu
Albert Cheung Hoi
AC
Sheu
Fwu-Shan
FS
D000818:Animals; D006152:Cyclic GMP / Q000037:antagonists & inhibitors / Q000502:physiology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D051668:Delayed Rectifier Potassium Channels / Q000187:drug effects* / Q000502:physiology; D004229:Dithiothreitol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D051379:Mice; D008815:Mice, Inbred Strains; D019579:Neocortex / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000494:pharmacology* / Q000502:physiology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010084:Oxidation-Reduction; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D015398:Signal Transduction; D013481:Superoxides / Q000494:pharmacology
D051668:Delayed Rectifier Potassium Channels; D020030:Nitric Oxide Donors; D013481:Superoxides; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP; D011188:Potassium; D004229:Dithiothreitol