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English Intro

ENGLISH VERSION

     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
 

 Publication List: 期刊論文 (since 1992):

  • Tai CH, Pan MK, Lin JJ, Huang CS, Yang YC, Kuo CC(2012)
    Subthalamic discharges as a causal determinant of parkinsonian motor deficits. Ann Neurol. 72(3):464-76.
  • Yang YC, Lin S, Chang PC, Lin HC, Kuo CC(2011) Functional extension of amino acid triads from the fourthtransmembrane segment (S4) into its external linker in Shaker K+ channels. J. Biol. Chem.
    286:37503-14
  • Tai, C.-H., Tang,Y.-C., Pan, M.-K., Huang, C.-S., Kuo, C.-C. (2011) Modulation of subthalamic T-type Ca2+ channels remedies locomotor deficits in a rat model of Parkinson disease. Journal of Clinical Investigation (in press)
  • Yang, Y.-C., Huang, C.-S., and Kuo C.-C. (2010) Lidocaine, carbamazepine, and imipramine have partially overlapping binding sites and additive inhibitory effect on neuronal Na+ channels. Anesthesiology 113:160-174
  • Yang YC, Lee CH, Kuo CC. (2010) Ionic flow enhances low-affinity binding: a revised mechanistic view into Mg2+ block of NMDA receptors. J Physiol. 588(Pt 4):633-50
  • Yang YC, Hsieh JK, Kuo, C.-C. (2009)The external pore loop interacts with S6 and S3-S4 linker in domain 4 to assume an essential role in gating control and anticonvulsant action in the Na+ channel. Journal of General Physiology 134: 95-113.
  • Chang, H. -R., and Kuo, C.-C. (2008) The activation gate and gating mechanism of the N-methyl-D-aspartate receptor. Journal of Neuroscience 28:1546-1556
  • Chang, H. -R., and Kuo, C.-C. (2008) Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor. Journal of Medicinal Chemistry 51:1534-1545
  • Yang YC, Own CJ, Kuo CC. (2007) A hydrophobic element secures S4 voltage sensor in position in resting Shaker K channels. The Journal of physiology. 582(Pt 3):1059-72.
  • Chang HR, Kuo CC. (2007) Extracellular proton-modulated pore-blocking effects of the anticonvulsant felbamate on NMDA channel. Biophysical journal. 93(6):1981-92.
  • Chang HR, Kuo CC. (2007) Characterization of the Gating Conformational Changes in the Felbamate Binding Site in NMDA Channels. Biophysical journal. 93(2):456-66.
  • Yang, Y. -C., and Kuo, C.-C. (2005) An inactivation stabilizer of the Na+ channel acts as an opportunistic pore blocker modulated by external Na+. Journal of General Physiology 125: 465-481.
  • Kuo, C.-C., Chen, W.-Y., and Yang, Y.-C. (2004) Block of tetrodotoxin-resistant Na+ channel pore by multivalent cations: gating modification and Na+ flow dependence. Journal of General Physiology 124: 27-42.
  • 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.
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Kuo, C.-C.(1998) Imipramine Inhibition of transient K+ current: an open-channel blocker preventing fast inactivation. Biophysical Journal 12:2845-2857
  • Kuo, C.-C. (1998) A common anticonvulsant binding site for phenytoin, carbamazepine, and lamotrigine in neuronal Na+ channels. Molecular Pharmacology 54:712-721
  • 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
  • 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
  • Kuo, C.-C. (1997) Deactivation retards recovery from inactivation in Shaker K+ channels. Journal of Neuroscience 17:3436-3444
  • 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
  • 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
  • Kuo, C.-C., and Bean, B.P. (1994) Na+ channels must deactivate to recover from inactivation. Neuron 12:819-829
  • Kuo, C.-C., and Bean, B.P. (1993) G-protein modulation of ion permeation through N-type calcium channels. Nature 365:258-262
  • 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
  • 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
  • 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
  • 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