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1 Department of Biological Sciences, National University of Singapore, Singapore, Singapore
2 Neuroscience Research Institute, Peking University, Beijing, China; Department of Neurobiology, Peking University Health Science Center, Beijing, China
3 Department of Biological Sciences, National University of Singapore, Singapore, Singapore; The University Scholars Programme, National University of Singapore, Singapore, Singapore
* To whom correspondence should be addressed. E-mail: dbssfs{at}nus.edu.sg.
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 (IK) and left the fast inactivating A current (IA) unchanged. However, high concentrations of SNAP (100 µM) and NO (0.5 µM) 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 (DTT), 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.
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