成員簡介

郭鐘金教授

郭鐘金教授
  • 郭鐘金

  • 職  稱:教授
  • 學  歷:美國哈佛大學 博士
  • 專  長:神經生理學和神經藥理學
  • 聯絡電話:(02)23123456 ext 288236
  • E-mail:chungchinkuo@ntu.edu.tw

郭鐘金教授—研究方向

  本實驗室之研究方向是離子通道之生理學與藥理學 ( Ion hannels:Physiology and Pharmacology )並希望能夠由之更深入瞭解各種具有興奮性之細胞,尤其是神經細胞,控制其電氣活動之原理與方法。

    對碩士班研究生的工作要求是希望在兩年內完成一個簡單的 project ( 約相當一般學術性雜誌上 short paper 一篇之份量 ),並表現對有關 ion channels 各基本生物物理及電生理原則之充份瞭解,而後畢業。對博士班研究生,則希望能夠在四至六年內,表現對ion channels各基本之生物物理與深入之分子運作邏輯之嫻熟掌握與靈活運用,並完成一項完整具系統性之project(約相當於一般學術性雜誌上 full article上2-3篇論文之份量),而後畢業。

Publication List: 期刊論文 (since 1992):

  1. Lee, L-N, Huang, C-S, Chuang, H-H, Lai, H-J, Yang, C-K, Yang, Y-C, and Kuo, C-C (2021) An electrophysiological perspective on Parkinson's disease: symptomatic pathogenesis and therapeutic approaches. J Biomed Sci. 28:85
  2. Chou, P, and Kuo, C.-C. (2021) Anticonvulsant vs. proconvulsant effect of in situ deep brain stimulation at the epileptogenic focus. Front Syst Neurosci.15:607450
  3. Lin, Y-C, Lai, Y-C, Chou, P, Hsueh, S-W, Lin, T-H, Huang, C-S, Wang, R-W, Yang, Y-C, and Kuo, C-C (2021) How can a Na+ channel inhibitor ameliorate seizures in Lennox-Gastaut syndrome? Ann Neurol. doi:10.1002/ana.26068
  4. Wang, G-H, Chou, P, Hsueh S-W, Yang, Y-C, and Kuo, C-C (2020) Glutamate transmission rather than cellular pacemaking propels excitatory-inhibitory resonance for ictogenesis in amygdala. Neurobiol Dis. 148:105188
  5. Chou, P, Wang, G-H, Hsieh, S-W, Yang, Y-C, and Kuo, C-C (2020) Delta-frequency augmentation and synchronization in seizure discharges and telencephalic transmission. iScience 23(11):101666
  6. Peng, Y-S, Wu, H-T, Lay, Y-C, Chen, J-L, Yang, Y-C, and Kuo, C-C (2020) Inhibition of neuronal Na+ currents by lacosamide: differential binding affinity and kinetics to different inactivated states. Neuropharmacology 179:108266
  7. Tai, C-H, Pan, M-K, Tseng, S-H, Wang, T-R, and Kuo, C.-C. (2020) Hyperpolarization of the subthalamic nucleus alleviates hyperkinetic movement disorders. Sci Rep.10:8278
  8. Wang, G-H, Chou, P, Hsueh S-W, Yang, Y-C, and Kuo, C-C (2020) Glutamate transmission rather than cellular pacemaking propels excitatory-inhibitory resonance for ictogenesis in amygdala. Neurobiol Dis. 148:105188
  9. Chou, P, Wang, G-H, Hsieh, S-W, Yang, Y-C, and Kuo, C-C (2020) Delta-frequency augmentation and synchronization in seizure discharges and telencephalic transmission. iScience 23(11):101666
  10. Peng, Y-S, Wu, H-T, Lay, Y-C, Chen, J-L, Yang, Y-C, and Kuo, C-C (2020) Inhibition of neuronal Na+ currents by lacosamide: differential binding affinity and kinetics to different inactivated states. Neuropharmacology 179:108266
  11. Tai, C-H, Pan, M-K, Tseng, S-H, Wang, T-R, and Kuo, C.-C. (2020) Hyperpolarization of the subthalamic nucleus alleviates hyperkinetic movement disorders. Sci Rep.10:8278
  12. Chen, Y-S, Tu, Y-C, Lai, Y-C, Liu, Erin, Yang, Y-C, and Kuo, C-C (2019) Desensitization of NMDA channels requires ligand binding to both GluN1 and GluN2 subunits to constrict the pore beside the activation gate. J Neurochem. 153(5):549-566
  13. Huang, C.-W., Lai, H.-J., Huang, P.-Y., Lee, M.-J., and Kuo, C.-C (2019) Anomalous enhancement of resurgent Na+ currents at high temperatures by SCN9A mutations underlies the episodic heat-enhanced pain in inherited erythromelalgia. Sci Rep. 9:12251
  14. Lo, Y.-T., and Kuo, C.-C. (2019) Temperature dependence of the biophysical mechanisms underlying the inhibition and enhancement effect of amiodarone on hERG channels. Mol Pharmacol. 96:330-344
  15. Chen, Y-S, Tu, Y-C, Lai, Y-C, Liu, Erin, Yang, Y-C, and Kuo, C-C (2019) Desensitization of NMDA channels requires ligand binding to both GluN1 and GluN2 subunits to constrict the pore beside the activation gate. J Neurochem. 153(5):549-566
  16. Huang, C.-W., Lai, H.-J., Huang, P.-Y., Lee, M.-J., and Kuo, C.-C (2019) Anomalous enhancement of resurgent Na+ currents at high temperatures by SCN9A mutations underlies the episodic heat-enhanced pain in inherited erythromelalgia. Sci Rep. 9:12251
  17. Lo, Y.-T., and Kuo, C.-C. (2019) Temperature dependence of the biophysical mechanisms underlying the inhibition and enhancement effect of amiodarone on hERG channels. Mol Pharmacol. 96:330-344
  18. Huang C-W, Kuo C-C. (2016) A synergistic blocking effect of Mg2+ and spermine on the inward rectifier K+ (Kir2.1) channel pore. Scientific Reports 6:21493
  19. Tu .-C, Yang Y-C, Kuo, C.-C. (2016) Modulation of NMDA channel gating by Ca2+ and Cd2+ binding to the external pore mouth. Scientific Reports (in press)
  20. Pan M-K, Kuo,S-H, Tai C-H, Liou J-Y, Pei J-C, Chang C-Y, WangY-M, Liu W-C, Wang T-R, Lai W-S, Kuo C-C (2016) Neuronal firing patterns outweigh circuitry oscillations in parkinsonian motor control. Journal of Clinical Investigation doi:10.1172/JCI88170
  21. Huang C-W, Lai, H.-J., Huang, P.-Y., Lee, M.-J., Kuo, C.-C. (2016) The biophysical basis underlying gating changes in the p.V1316A mutant Nav1.7 channel and the molecular pathogenesis of inherited erythromelalgia. PLoS Biology 14(9): e1002561.
  22. Tu, Y.-C., Kuo, C.-C. (2015) The differential contribution of GluN1 and GluN2 to the gating operation of the NMDA receptor channel. Pflugers Arch - Eur J Physiology (in press, DOI 10.1007/s00424-014-1630-z)
  23. Huang, C-W, Kuo C-C (2015) Flow- and voltage-dependent blocking effect of ethosuximide on the inward rectifier K+ (Kir2.1) channel. <http://www.ncbi.nlm.nih.gov/pubmed/25220134> Pflugers Arch - Eur J Physiology (in press, DOI: 10.1007/s00424-014-1611-2)
  24. Pan M-K, Tai C-H, Lin W-C, Pei J-C, Lai W-S, Kuo C-C (2014) Deranged NMDAergic cortico-subthalamic transmission underlies parkinsonian motor deficits. Journal of Clinical Investigation 124(10):4629-4641
  25. Huang C-W, Kuo C-C (2014) Gating of the Kir2.1 channel at the bundle crossing region by spermine and other intracellular cations. Journal of Cellular Physiology 229(11):1703-21
  26. Yang Y-C, Tai C-H, Pan M-K, Kuo C-C (2014) The T-type calcium channel as a new therapeutic target for Parkinson’s disease. Pflugers Arch- Eur J Physiology 466:747-755
  27. Huang C-W, Kuo C-C (2014) The bundle crossing region is responsible for the inwardly rectifying internal spermine block of the Kir2.1 channel. Pflugers Arch - Eur J Physiology 466 (2):275-293
  28. Tai C-H, Pan M-K, Lin J-J, Huang C-S, Yang Y-C, Kuo C-C(2012)
    Subthalamic discharges as a causal determinant of parkinsonian motor deficits. Ann Neurol. 72(3):464-76.
  29. 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
  30. 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)
  31. 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
  32. 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
  33. 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.
  34. 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
  35. 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
  36. 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.
  37. Chang HR, Kuo CC. (2007) Extracellular proton-modulated pore-blocking effects of the anticonvulsant felbamate on NMDA channel. Biophysical journal. 93(6):1981-92.
  38. 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.
  39. 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.
  40. 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.
  41. 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.
  42. 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
  43. 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
  44. 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
  45. 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
  46. 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
  47. 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
  48. 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
  49. 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
  50. Kuo, C.-C.(1998) Imipramine Inhibition of transient K+ current: an open-channel blocker preventing fast inactivation. Biophysical Journal 12:2845-2857
  51. Kuo, C.-C. (1998) A common anticonvulsant binding site for phenytoin, carbamazepine, and lamotrigine in neuronal Na+ channels. Molecular Pharmacology 54:712-721
  52. 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
  53. 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
  54. Kuo, C.-C. (1997) Deactivation retards recovery from inactivation in Shaker K+ channels. Journal of Neuroscience 17:3436-3444
  55. 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
  56. 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
  57. Kuo, C.-C., and Bean, B.P. (1994) Na+ channels must deactivate to recover from inactivation. Neuron 12:819-829
  58. Kuo, C.-C., and Bean, B.P. (1993) G-protein modulation of ion permeation through N-type calcium channels. Nature 365:258-262
  59. 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
  60. 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
  61. 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
  62. 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

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):

  1. 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.
  2. 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
  3. 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)
  4. 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
  5. 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
  6. 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.
  7. 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
  8. 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
  9. 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.
  10. Chang HR, Kuo CC. (2007) Extracellular proton-modulated pore-blocking effects of the anticonvulsant felbamate on NMDA channel. Biophysical journal. 93(6):1981-92.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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
  16. 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
  17. 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
  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. 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
  20. 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
  21. 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
  22. 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
  23. Kuo, C.-C.(1998) Imipramine Inhibition of transient K+ current: an open-channel blocker preventing fast inactivation. Biophysical Journal 12:2845-2857
  24. Kuo, C.-C. (1998) A common anticonvulsant binding site for phenytoin, carbamazepine, and lamotrigine in neuronal Na+ channels. Molecular Pharmacology 54:712-721
  25. 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
  26. 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
  27. Kuo, C.-C. (1997) Deactivation retards recovery from inactivation in Shaker K+ channels. Journal of Neuroscience 17:3436-3444
  28. 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
  29. 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
  30. Kuo, C.-C., and Bean, B.P. (1994) Na+ channels must deactivate to recover from inactivation. Neuron 12:819-829
  31. Kuo, C.-C., and Bean, B.P. (1993) G-protein modulation of ion permeation through N-type calcium channels. Nature 365:258-262
  32. 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
  33. 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
  34. 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
  35. 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

博士班學生

王人偉
李嵐忻
賴星融

碩士班學生

姜鈞喨
高辰瑋
莊定榮
蘇偉銘

研究助理

李卓明
陳建霖