My colleagues and I are interested in understanding the behavior of ion channels, important membrane proteins controlling the excitability of neurons and other excitable cells. Recently we have focused on the gating mechanisms of A-type potassium channels (transient outward potassium currents) in both native cells and cloned channels. We have also been investigating the molecular action of anticonvulsant drugs on sodium channels in mammalian central neurons. We found that the opening (activation) of A-channels seems to involve conformational changes in the external pore mouth, and that the conformational changes at the internal pore mouth during recovery from inactivation are very different in sodium and in A-type potassium channels. We also found that the commonly prescribed anticonvulsants phenytoin, carbamazepine, and lamotrigine all selectively bind to the same anticonvulsant binding site in the fast inactivated state of neuronal sodium channels with very slow binding kinetics. The qualitatively similar action of these drugs, however, is qualitatively very different. For example, the binding affinity between inactivated sodium channels and phenytoin is ~3 times higher than that of carbamazepine, yet the binding rate for carbamazepine is ~5 times faster than phenytoin. Thus carbamazepine could be more effective against seizures whose ictal depolarization is relatively short or not repeated at high frequency, while a better response to phenytoin may indicate seizure discharges characterized by relatively prolonged depolarization. These findings may be contributory both to a more sophisticated use of the medication and to the characterization of the manifold cellular attributes of human epilepsy. Moreover, characterization of the interaction between commonly prescribed drugs and ion channels would be informative on the molecular behavior of channels considering the state-dependent action of the drug.
PUBLICATIONS since 1992
1. Kuo, C.-C., and Hess, P. (1992) A functional view of the entrances of L-type Ca2+ channels: estimates of the size and surface potential at the pore mouths. Neuron 9:515-526
2. Kuo, C.-C., and Hess, P. (1993) Ion permeation through the L-type Ca2+ channel in rat phaeochromocytoma cells: two sets of ion binding sites in the pore. Journal of Physiology 466:629-655
3. Kuo, C.-C., and Hess, P. (1993) Characterization of the high-affinity Ca2+ binding sites in the L-type Ca2+ channel pore in rat phaeochromocytoma cells. Journal of Physiology 466:657-682
4. Kuo, C.-C., and Hess, P. (1993) Block of the L-type Ca2+ channel pore by external and internal Mg2+ in rat phaeochromocytoma cells. Journal of Physiology 466:683-706
5. Kuo, C.-C., and Bean, B.P. (1993) G-protein modulation of ion permeation through N-type calcium channels. Nature 365:258-262
6. Kuo, C.-C., and Bean, B.P. (1994) Na+ channels must deactivate to recover from inactivation. Neuron 12:819-829
7. Kuo, C.-C., and Bean, B.P. (1994) Slow binding of phenytoin to inactivated sodium channels in rat hippocampal neurons. Molecular Pharmacology 46:716-725
8. Geula, C., Mesulam, M.-M., Kuo, C.-C., and Tokuno, H. (1995) Postnatal development of cortical acetylcholinesterase-rich neurons in the rat brain: permanent and transient patterns. Experimental Neurology 134:157-178
9. Kuo, C.-C. (1997) Deactivation retards recovery from inactivation in Shaker K+ channels. Journal of Neuroscience 17:3436-3444
10. Kuo, C.-C., Chen, R.-S., Lu, L., and Chen, R.-C. (1997) Carbamazepine inhibition of neuronal Na+ currents: quantitative distinction from phenytoin and possible therapeutic implications. Molecular Pharmacology 51:1077-1083
11. Kuo, C.-C., and Lu, L. (1997) Characterization of lamotrigine inhibition of Na+ channels in rat hippocampal neurons. British Journal of Pharmacology 121:1231-1238
12. Kuo, C.-C. (1998) A common anticonvulsant binding site for phenytoin, carbamazepine, and lamotrigine in neuronal Na+ channels. Molecular Pharmacology 54:712-721
13. Kuo, C.-C. (1998) Imipramine Inhibition of transient K+ current: an open-channel blocker preventing fast inactivation. Biophysical Journal 12:2845-2857
14. Shieh, R.-C., Chang, J.-C., and Kuo, C.-C. (1999) K+ binding sites and interactions between permeating K+ ions at the external pore mouth of an inward rectifier K+ channel (Kir2.1). Journal of Biological Chemistry 274:17424-17430
15. Kuo, C.-C., and Chen F.-P. (1999) Zn+ modulation of neuronal transient K+ current: fast and selective binding to the deactivated channels. Biophysical Journal 77:2552-2562
16. Kuo, C.-C., Huang, R.-C., and Lou, B.-S. (2000) Inhibition of Na+ current by diphenhydramine and other diphenyl compounds: molecular determinants of selective binding to the inactivated channels. Molecular Pharmacology 57:135-143
17. Kuo, C.-C., and Liao, S.-Y. (2000) Facilitation of recovery from inactivation by external Na+ and location of the activation gate in neuronal Na+ channels. Journal of Neuroscience 20:5639-5646
18. Kuo, C.-C., and Yang, S. (2001) Recovery from inactivation of T-type Ca2+ channels in rat thalamic neurons. Journal of Neuroscience 21:1884-1892
19.Yang, Y.-C., and Kuo, C.-C. (2002) Inhibition of Na+ current by imipramine and related compounds: different binding kinetics as an inactivation stabilizer and as an open channel blocker. molecular Pharmacology 62:1228-1237
20.Kuo, C.-C., Lin, T.-J., and Hsieh, C.-P. (2002) Effect of Na+ flow on cd2+ block of tetrodotoxin-resistant Na+ channels. Journal of General Physiology 120:159-172
21.Yang, Y.-C, and Kuo, C.-C. (2003) The position of the fourth segment of domain 4 determines status of the inactivation fate in Na+ channels. Journal of Neuroscience 23: 4922-4930
22.Kuo, C.-C., Lin, B.-J., Chang, H.-R., and Hsieh, C.-P.(2004) Use-dependent inhibition of the N-Methy-D-asparate currents by felbamate: a gating modifier with selective binding to the desensitized channels. molecular Pharmacology 65: 370-380.
23.Kuo, C.-C., Chen, W.-Y., and Yang, Y.-C. Yang. (2004) Block of tetrodotoxin-resistant Na+ channel pore by multivalent cations: gating modification and Na+ flow dependence. Journal of General Physiology 124: 27-42.