請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/65469
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 郭鐘金 | |
dc.contributor.author | Chih-Hung Lin | en |
dc.contributor.author | 林志鴻 | zh_TW |
dc.date.accessioned | 2021-06-16T23:44:57Z | - |
dc.date.available | 2015-09-19 | |
dc.date.copyright | 2012-09-19 | |
dc.date.issued | 2012 | |
dc.date.submitted | 2012-07-24 | |
dc.identifier.citation | 參考文獻
Akhavan A, Atanasiu R, Noguchi T, Han W, Holder N, Shrier A (2005) Identification of the cyclic-nucleotide-binding domain as a conserved determinant of ion-channel cell-surface localization. J Cell Sci 118:2803-2812. Anantharam A, Markowitz SM, Abbott GW (2003) Pharmacogenetic Considerations in Diseases of Cardiac Ion Channels. Journal of Pharmacology and Experimental Therapeutics 307:831-838. Armstrong CM (1966) Time Course of TEA+-Induced Anomalous Rectification in Squid Giant Axons. The Journal of General Physiology 50:491-503. Armstrong CM (1969) Inactivation of the potassium conductance and related phenomena caused by quaternary ammonium ion injection in squid axons. J Gen Physiol 54:553-575. Armstrong CM (1971) Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axons. J Gen Physiol 58:413-437. Asher V, Sowter H, Shaw R, Bali A, Khan R (2010) Eag and HERG potassium channels as novel therapeutic targets in cancer. World Journal of Surgical Oncology 8:113. Bauer CK, Schwarz JR (2001) Physiology of EAG K+ Channels. Journal of Membrane Biology 182:1-15. Bett Glenna CL, Zhou Q, Rasmusson Randall L (2011) Models of HERG Gating. Biophysical Journal 101:631-642. Bian J, Cui J, McDonald TV (2001) HERG K+ Channel Activity Is Regulated by Changes in Phosphatidyl Inositol 4,5-Bisphosphate. Circulation Research 89:1168-1176. Biggin PC, Roosild T, Choe S (2000) Potassium channel structure: domain by domain. Current Opinion in Structural Biology 10:456-461. Boyd S, Bryson A, Nancollas GH, Torrance K (1965) 1349. Thermodynamics of ion association. Part XII. EGTA complexes with divalent metal ions. Journal of the Chemical Society (Resumed) 7353. Brelidze TI, Carlson AE, Zagotta WN (2009) Absence of Direct Cyclic Nucleotide Modulation of mEAG1 and hERG1 Channels Revealed with Fluorescence and Electrophysiological Methods. Journal of Biological Chemistry 284:27989-27997. Cabral JHM, Lee A, Cohen SL, Chait BT, Li M, Mackinnon R (1998) Crystal Structure and Functional Analysis of the HERG Potassium Channel N Terminus: A Eukaryotic PAS Domain. Cell 95:649-655. Camacho J (2006) Ether à go-go potassium channels and cancer. Cancer Letters 233:1-9. Chen J, Seebohm G, Sanguinetti MC (2002) Position of aromatic residues in the S6 domain, not inactivation, dictates cisapride sensitivity of HERG and eag potassium channels. Proceedings of the National Academy of Sciences 99:12461-12466. Cheng JH, Kodama I (2004) Two components of delayed rectifier K+ current in heart: molecular basis, functional diversity, and contribution to repolarization. Acta Pharmacol Sin 25:137-145. Choi KH, Song C, Shin D, Park S (2011) hERG channel blockade by externally applied quaternary ammonium derivatives. Biochim Biophys Acta 1808:1560-1566. Choi KL, Aldrich RW, Yellen G (1991) Tetraethylammonium blockade distinguishes two inactivation mechanisms in voltage-activated K+ channels. Proceedings of the National Academy of Sciences 88:5092-5095. Choi KL, Mossman C, Aube J, Yellen G (1993) The internal quaternary ammonium receptor site of Shaker potassium channels. Neuron 10:533-541. Clancy CE, Kurokawa J, Tateyama M, Wehrens XHT, Kass RS (2003) K+ CHANNEL STRUCTURE-ACTIVITY RELATIONSHIPS AND MECHANISMS OF DRUG-INDUCED QT PROLONGATION. Annual Review of Pharmacology and Toxicology 43:441-461. Clancy CE, Rudy Y (2001) Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death. Cardiovascular Research 50:301-313. Cui J, Melman Y, Palma E, Fishman GI, McDonald TV (2000) Cyclic AMP regulates the HERG K+ channel by dual pathways. Current Biology 10:671-674. Curran ME, Splawski I, Timothy KW, Vincen GM, Green ED, Keating MT (1995) A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 80:795-803. Diochot S, Loret E, Bruhn T, Béress L, Lazdunski M (2003) APETx1, a New Toxin from the Sea Anemone Anthopleura elegantissima, Blocks Voltage-Gated Human Ether-a-go-go–Related Gene Potassium Channels. Molecular Pharmacology 64:59-69. Fakler B, Brändle U, Bond C, Glowatzki E, König C, Adelman JP, Zenner HP, Ruppersberg JP (1994) A structural determinant of differential sensitivity of cloned inward rectifier K+ channels to intracellular spermine. FEBS Letters 356:199-203. Fakler B, Brändle U, Glowatzki E, Weidemann S, Zenner HP, Ruppersberg JP (1995) Strong voltage-dependent inward rectification of inward rectifier K+ channels is caused by intracellular spermine. Cell 80:149-154. Fernandez D, Sargent J, Sachse FB, Sanguinetti MC (2008) Structural Basis for Ether-a-go-go-Related Gene K+ Channel Subtype-Dependent Activation by Niflumic Acid. Molecular Pharmacology 73:1159-1167. Ficker E, Obejero-Paz CA, Zhao S, Brown AM (2002) The Binding Site for Channel Blockers That Rescue Misprocessed Human Long QT Syndrome Type 2 ether-a-gogo-related Gene (HERG) Mutations. Journal of Biological Chemistry 277:4989-4998. Ficker E, Taglialatela M, Wible BA, Henley CM, Brown AM (1994) Spermine and spermidine as gating molecules for inward rectifier K+ channels. Science 266:1068-1072. French RJ, Shoukimas JJ (1981) Blockage of squid axon potassium conductance by internal tetra-N-alkylammonium ions of various sizes. Biophysical Journal 34:271-291. Ganetzky B, Robertson GA, Wilson GF, Trudeau MC, Titus SA (1999) The eag family of K+ channels in Drosophila and mammals. Ann N Y Acad Sci 868:356-369. Goldstein SAN, Wang KW, Ilan N, Pausch MH (1998) Sequence and function of the two P domain potassium channels: implications of an emerging superfamily. Journal of Molecular Medicine 76:13-20. Greenstein JL, Wu R, Po S, Tomaselli GF, Winslow RL (2000) Role of the Calcium-Independent Transient Outward Current Ito1 in Shaping Action Potential Morphology and Duration. Circulation Research 87:1026-1033. Gurdon JB, Lane CD, Woodland HR, Marbaix G (1971) Use of Frog Eggs and Oocytes for the Study of Messenger RNA and its Translation in Living Cells. Nature 233:177-182. Gutman GA (2005) International Union of Pharmacology. LIII. Nomenclature and Molecular Relationships of Voltage-Gated Potassium Channels. Pharmacological Reviews 57:473-508. Haverkamp W, Breithardt G, Camm AJ, Janse MJ, Rosen MR, Antzelevitch C, Escande D, Franz M, Malik M, Moss A, Shah R (2000) The potential for QT prolongation and pro-arrhythmia by non-anti-arrhythmic drugs: Clinical and regulatory implications. Cardiovascular Research 47:219-233. Heginbotham L, MacKinnon R (1992) The aromatic binding site for tetraethylammonium ion on potassium channels. Neuron 8:483-491. Hodgkin AL, Huxley AF (1952) A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol 117:500-544. Hoshi T, Zagotta WN, Aldrich RW (1991) Two types of inactivation in Shaker K+ channels: Effects of alterations in the carboxy-terminal region. Neuron 7:547-556. Imbrici P, Grottesi A, D'Adamo MC, Mannucci R, Tucker SJ, Pessia M (2009) Contribution of the central hydrophobic residue in the PXP motif of voltage-dependent K<sup>+</sup> channels to S6 flexibility and gating properties. Channels 3:39-45. Jamieson C, Moir EM, Rankovic Z, Wishart G (2006) Medicinal chemistry of hERG optimizations: Highlights and hang-ups. J Med Chem 49:5029-5046. Jo SH, Hong HK, Jung SJ, Chong SH, Yun JH, Koh YS, Choe H (2007) Maprotiline block of the human ether-a-go-go-related gene (HERG) K+ channel. Arch Pharm Res 30:453-460. Kamiya K, Mitcheson JS, Yasui K, Kodama I, Sanguinetti MC (2001) Open Channel Block of HERG K+ Channels by Vesnarinone. Molecular Pharmacology 60:244-253. Kavanaugh M, Varnum M, Osborne P, Christie M, Busch A, Adelman J, North R (1991) Interaction between tetraethylammonium and amino acid residues in the pore of cloned voltage-dependent potassium channels. J Biol Chem 266:7583-7587. Kiehn J, Lacerda AE, Brown AM (1999) Pathways of HERG inactivation. American Journal of Physiology - Heart and Circulatory Physiology 277:H199-H210. Kiehn J, Lacerda AE, Wible B, Brown AM (1996) Molecular Physiology and Pharmacology of HERG: Single-Channel Currents and Block by Dofetilide. Circulation 94:2572-2579. KUMÁNOVICS A, LEVIN G, BLOUNT P (2002) Family ties of gated pores: evolution of the sensor module. The FASEB Journal 16:1623-1629. Lees-Miller JP, Duan Y, Teng GQ, Duff HJ (2000) Molecular Determinant of High-Affinity Dofetilide Binding toHERG1 Expressed in Xenopus Oocytes: Involvement of S6 Sites. Molecular Pharmacology 57:367-374. Liu J, Zhang M, Jiang M, Tseng G-N (2003) Negative Charges in the Transmembrane Domains of the HERG K Channel Are Involved in the Activation- and Deactivation-gating Processes. The Journal of General Physiology 121:599-614. Liu S, Rasmusson RL, Campbell DL, Wang S, Strauss HC (1996) Activation and inactivation kinetics of an E-4031-sensitive current from single ferret atrial myocytes. Biophysical Journal 70:2704-2715. London B, Trudeau MC, Newton KP, Beyer AK, Copeland NG, Gilbert DJ, Jenkins NA, Satler CA, Robertson GA (1997) Two isoforms of the mouse ether-a-go-go-related gene coassemble to form channels with properties similar to the rapidly activating component of the cardiac delayed rectifier K+ current. Circ Res 81:870-878. Lu Z, MacKinnon R (1994) Electrostatic tuning of Mg2+ affinity in an inward-rectifier K+ channel. Nature 371:243-246. Malykhina AP, Shoeb F, Akbarali HI (2002) Fenamate-induced enhancement of heterologously expressed HERG currents in Xenopus oocytes. European Journal of Pharmacology 452:269-277. Mazhari R, Greenstein JL, Winslow RL, Marban E, Nuss HB (2001) Molecular Interactions Between Two Long-QT Syndrome Gene Products, HERG and KCNE2, Rationalized by In Vitro and In Silico Analysis. Circulation Research 89:33-38. Mazzanti M, DiFrancesco D (1989) Intracellular Ca modulates K-inward rectification in cardiac myocytes. Pflügers Archiv European Journal of Physiology 413:322-324. Miller C (2000) An overview of the potassium channel family. Genome Biology 1:reviews0004.0001 - reviews0004.0005. Milnes JT, Crociani O, Arcangeli A, Hancox JC, Witchel HJ (2003a) Blockade of HERG potassium currents by fluvoxamine: incomplete attenuation by S6 mutations at F656 or Y652. British Journal of Pharmacology 139:887-898. Milnes JT, Dempsey CE, Ridley JM, Crociani O, Arcangeli A, Hancox JC, Witchel HJ (2003b) Preferential closed channel blockade of HERG potassium currents by chemically synthesised BeKm-1 scorpion toxin. FEBS Letters 547:20-26. Mitcheson JS (2003) Drug binding to HERG channels: evidence for a ‘non-aromatic’ binding site for fluvoxamine. British Journal of Pharmacology 139:883-884. Mitcheson JS, Chen J, Lin M, Culberson C, Sanguinetti MC (2000a) A structural basis for drug-induced long QT syndrome. Proceedings of the National Academy of Sciences 97:12329-12333. Mitcheson JS, Chen J, Sanguinetti MC (2000b) Trapping of a Methanesulfonanilide by Closure of the Herg Potassium Channel Activation Gate. The Journal of General Physiology 115:229-240. Miyake A, Mochizuki S, Yokoi H, Kohda M, Furuichi K (1999) New Ether-à-go-go K+ Channel Family Members Localized in Human Telencephalon. Journal of Biological Chemistry 274:25018-25025. Murata Y, Iwasaki H, Sasaki M, Inaba K, Okamura Y (2005) Phosphoinositide phosphatase activity coupled to an intrinsic voltage sensor. Nature 435:1239-1243. Muskett FW, Thouta S, Thomson SJ, Bowen A, Stansfeld PJ, Mitcheson JS (2010) Mechanistic Insight into Human ether-a-go-go-related Gene (hERG) K+ Channel Deactivation Gating from the Solution Structure of the EAG Domain. Journal of Biological Chemistry 286:6184-6191. Noemí BS (2006) The ether-a-go-go Related Gene (erg) Voltage-Gated K+ Channels: A Common Structure With Uncommon Characteristics. Oehmen CS, Giles WR, Demir SS (2002) Mathematical Model of the Rapidly Activating Delayed Rectifier Potassium Current IKr in Rabbit Sinoatrial Node. Journal of Cardiovascular Electrophysiology 13:1131-1140. Overholt JL, Ficker E, Yang T, Shams H, Bright GR, Prabhakar NR (2000) HERG-Like Potassium Current Regulates the Resting Membrane Potential in Glomus Cells of the Rabbit Carotid Body. Journal of Neurophysiology 83:1150-1157. Pellequer JL, Brudler R, Getzoff ED (1999) Biological sensors: More than one way to sense oxygen. Current Biology 9:R416-R418. Perrin MJ, Subbiah RN, Vandenberg JI, Hill AP (2008) Human ether-a-go-go related gene (hERG) K+ channels: Function and dysfunction. Progress in Biophysics and Molecular Biology 98:137-148. Piper DR, Varghese A, Sanguinetti MC, Tristani-Firouzi M (2003) Gating currents associated with intramembrane charge displacement in HERG potassium channels. Proceedings of the National Academy of Sciences 100:10534-10539. Ponting CP, Aravind L (1997) PAS: a multifunctional domain family comes to light. Curr Biol 7:R674-677. Rasmusson RL, Morales MJ, Wang S, Liu S, Campbell DL, Brahmajothi MV, Strauss HC (1998) Inactivation of Voltage-Gated Cardiac K+ Channels. Circulation Research 82:739-750. Recanatini M, Poluzzi E, Masetti M, Cavalli A, De Ponti F (2005) QT prolongation through hERG K(+) channel blockade: current knowledge and strategies for the early prediction during drug development. Med Res Rev 25:133-166. Rodriguez N, Amarouch MY, Montnach J, Piron J, Labro AJ, Charpentier F, Mérot J, Baró I, Loussouarn G (2010) Phosphatidylinositol-4,5-Bisphosphate (PIP2) Stabilizes the Open Pore Conformation of the Kv11.1 (hERG) Channel. Biophysical Journal 99:1110-1118. Sánchez-Chapula JA, Navarro-Polanco RA, Culberson C, Chen J, Sanguinetti MC (2002) Molecular Determinants of Voltage-dependent Human Ether-a-Go-Go Related Gene (HERG) K+ Channel Block. Journal of Biological Chemistry 277:23587-23595. Sănchez-Chapula JA, Ferrer T, Navarro-Polanco RA, Sanguinetti MC (2003) Voltage-Dependent Profile of HumanEther-a-go-go-Related Gene Channel Block Is Influenced by a Single Residue in the S6 Transmembrane Domain. Molecular Pharmacology 63:1051-1058. Sanguinetti M (2010) HERG1 channelopathies. Pflügers Archiv European Journal of Physiology 460:265-276. Sanguinetti MC, Jiang C, Curran ME, Keating MT (1995) A mechanistic link between an inherited and an acquird cardiac arrthytmia: HERG encodes the IKr potassium channel. Cell 81:299-307. Sanguinetti MC, Jurkiewicz NK (1990) Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol 96:195-215. Sanguinetti MC, Tristani-Firouzi M (2006) hERG potassium channels and cardiac arrhythmia. Nature 440:463-469. Sasaki M, Takagi M, Okamura Y (2006) A Voltage Sensor-Domain Protein Is a Voltage-Gated Proton Channel. Science 312:589-592. Schwarz JR, Bauer CK (2004) Functions of erg K+ channels in excitable cells. J Cell Mol Med 8:22-30. Seoh S-A, Sigg D, Papazian DM, Bezanilla F (1996) Voltage-Sensing Residues in the S2 and S4 Segments of the Shaker K+ Channel. Neuron 16:1159-1167. Shen NV, Pfaffinger PJ (1995) Molecular recognition and assembly sequences involved in the subfamily-specific assembly of voltage-gated K+ channel subunit proteins. Neuron 14:625-633. Shepard PD, Canavier CC, Levitan ES (2006) Ether-a-go-go Related Gene Potassium Channels: What's All the Buzz About? Schizophrenia Bulletin 33:1263-1269. Shibasaki T (1987) Conductance and kinetics of delayed rectifier potassium channels in nodal cells of the rabbit heart. J Physiol 387:227-250. Smith PL, Baukrowitz T, Yellen G (1996) The inward rectification mechanism of the HERG cardiac potassium channel. Nature 379:833-836. Smith PL, Yellen G (2002) Fast and Slow Voltage Sensor Movements in HERG Potassium Channels. The Journal of General Physiology 119:275-293. Snyders DJ, Chaudhary A (1996) High affinity open channel block by dofetilide of HERG expressed in a human cell line. Molecular Pharmacology 49:949-955. Spector PS, Curran ME, Keating MT, Sanguinetti MC (1996a) Class III Antiarrhythmic Drugs Block HERG, a Human Cardiac Delayed Rectifier K+ Channel : Open-Channel Block by Methanesulfonanilides. Circulation Research 78:499-503. Spector PS, Curran ME, Zou A, Keating MT, Sanguinetti MC (1996b) Fast inactivation causes rectification of the IKr channel. The Journal of General Physiology 107:611-619. Swenson RP, Jr. (1981) Inactivation of potassium current in squid axon by a variety of quaternary ammonium ions. J Gen Physiol 77:255-271. Taylor BL, Zhulin IB (1999) PAS domains: internal sensors of oxygen, redox potential, and light. Microbiol Mol Biol Rev 63:479-506. Thomas D, Wendt-Nordahl G, Röckl K, Ficker E, Brown AM, Kiehn J (2001) High-Affinity Blockade of Human Ether-A-Go-Go-Related Gene Human Cardiac Potassium Channels by the Novel Antiarrhythmic Drug BRL-32872. Journal of Pharmacology and Experimental Therapeutics 297:753-761. Trudeau M, Warmke J, Ganetzky B, Robertson G (1995) HERG, a human inward rectifier in the voltage-gated potassium channel family. Science 269:92-95. Tseng G-N (2001) IKr: The hERG Channel. Journal of Molecular and Cellular Cardiology 33:835-849. Vandenberg CA (1987) Inward rectification of a potassium channel in cardiac ventricular cells depends on internal magnesium ions. Proc Natl Acad Sci U S A 84:2560-2564. Vandenberg JI, Torres AM, Campbell TJ, Kuchel PW (2004) The HERG K+ channel: progress in understanding the molecular basis of its unusual gating kinetics. Eur Biophys J 33:89-97. Vivienne Shen N, Chen X, Boyer MM, Pfaffinger PJ (1993) Deletion analysis of K+ channel assembly. Neuron 11:67-76. Wang S, Liu S, Morales MJ, Strauss HC, Rasmusson RL (1997) A quantitative analysis of the activation and inactivation kinetics of HERG expressed in Xenopus oocytes. The Journal of Physiology 502:45-60. Warmke J, Drysdale R, Ganetzky B (1991) A distinct potassium channel polypeptide encoded by the Drosophila eag locus. Science 252:1560-1562. Warmke JW, Ganetzky B (1994) A family of potassium channel genes related to eag in Drosophila and mammals. Proc Natl Acad Sci U S A 91:3438-3442. Wible BA, Taglialatela M, Ficker E, Brown AM (1994) Gating of inwardly rectifying K+ channels localized to a single negatively charged residue. Nature 371:246-249. Yellen G (2002) The voltage-gated potassium channels and their relatives. Nature 419:35-42. Zeng J, Laurita KR, Rosenbaum DS, Rudy Y (1995) Two Components of the Delayed Rectifier K+ Current in Ventricular Myocytes of the Guinea Pig Type : Theoretical Formulation and Their Role in Repolarization. Circulation Research 77:140-152. Zhen (2010) HERG K+ channel related chemosensitivity to sparfloxacin in colon cancer cells. Oncology Reports 23. Zou A, Curran ME, Keating MT, Sanguinetti MC (1997) Single HERG delayed rectifier K+ channels expressed in Xenopus oocytes. American Journal of Physiology - Heart and Circulatory Physiology 272:H1309-H1314. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/65469 | - |
dc.description.abstract | 心臟跳動的節率被許多離子通道所調節,其中 human ether-à-go-go-related gene-1 (hERG1) 鉀離子通道扮演著重要的角色。hERG1通道回返電流的發生可促使心肌動作電位進行到再極化的階段,使心肌電位回到靜止膜電位,進而行使心臟正常的生理功能。不過,當hERG1通道發生點突變時,便會造成Long QT syndrome。Long QT syndrome 是很嚴重的疾病,一旦發生時很容易導致人體產生心律不整、甚至是死亡的危險。過去的研究指出,有些藥物可以抑制hERG1通道之電流,並因而有機會引發Long QT syndrome。最近的研究也報導,在hERG1通道外部添加常見的鉀離子通道抑制劑季銨鹽衍生物 (quaternary ammonium derivatives, QAs),會依據QAs不同的疏水性,而對hERG1通道電流的抑制效果及其inactivation有不同程度的影響。不過,過去還沒有研究藉由內部添加QAs,來探討hERG1通道內部孔洞的性質。因此,我們此篇論文的研究目的便是藉由分別添加QAs在hERG1通道的外部和內部,來探討hERG1通道外部孔洞和內部孔洞性質上的差異,並嘗試著解釋QAs如何抑制hERG1通道和影響其gating。我們發現內部添加QAs對於hERG1通道回返電流的抑制效果,比從外部添加快很多,而且抑制作用與復極化電位及其前置之去極化電位皆有相關。我們也發現,不同大小的QAs對於hERG1通道的作用有顯著的不同,各QA中以tetrahexylammonium (THxA) 最強,較大或較小之QA作用皆減弱。若改由細胞外投給QA,亦可見對hERG1 channel有抑制作用,其中亦以THxA最強,不過其親和力低於細胞內投與者的十倍以上。我們同時也發現,細胞內之多胺離子 (例如spermine) 對於hERG1 通道電流亦有顯著之抑制作用。這些發現顯示hERG1通道之內口區與外口區,在其開關以致產生回返電流之過程中,應該都有重要的型態變化。 | zh_TW |
dc.description.abstract | The human ether-à-go-go-related gene-1 (hERG1) potassium channel plays an important role in the regulation of cardiac rhythm. The resurgent currents through hERG1 channel contributes significantly to the repolarization phase of the cardiac action potential. Mutations or block of hERG1 channel may cause Long QT syndrome, a severe form of cardiac arrhythmia with a high incidence of sudden death. It has been shown that externally applied quaternary ammonium derivatives (QAs), a group of well-known potassium channel blockers, inhibit hERG1 channel current and affect inactivation of hERG1 channel according to their hydrophobicity. However, the effect of internally applied QAs has not been explored despite that some key gating conformational changes may involve the inner part of the pore. We first applied QAs on outside of hERG1 channel to confirm the previous findings on external QA block of hERG1 channel. We then perfused QAs to the internal side of the membrane with the inside-out patch configuration. We found that the blocking effect of internally applied QAs on the hERG1 channel happens much faster than external QAs. Moreover, the blocking effect of internal QAs is closely dependent on the voltage of the repolarization as well as the preceding depolarization phase. There are different inhibitory effects of QAs of different size. Tetrahexylammonium (THxA) has the strongest effect and the other QAs of the smaller or larger size all show weaken effect on hERG1 currents. For the externally applied QAs, THxA also has the sharpest effect. However, the blocking potency is in generally 10-fold smaller than internal QA. In the meanwhile, we demonstrate that internal polyamines (e.g. spermine) also have an inhibitory effect on the resurgent hERG1 currents. We conclude that there must be significant gating conformational changes associated with the genesis of the resurgent hERG1 currents in both the internal and external pore mouths of the hERG1 channel. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T23:44:57Z (GMT). No. of bitstreams: 1 ntu-101-R99441015-1.pdf: 3133221 bytes, checksum: d236d512fa86c483c5699b8769a7f76b (MD5) Previous issue date: 2012 | en |
dc.description.tableofcontents | 第一章 導論……………………………………………………………………….....1
第一節 電壓依賴性鉀離子通道概論………………………………………….1 第二節 Human ether-à-go-go Related Gene (hERG1) channel結構特色…......2 第三節 hERG1 channel生理重要性…………………………………………...4 第四節 hERG1 channel生物物理性質…………………......………………….4 第五節 不同藥物對hERG1 channel外部孔洞的影響…………..…..……...…9 第六節 不同藥物對hERG1 channel內部孔洞的影響……………………….10 第七節 實驗研究目的……………………………………………...…………12 第二章 材料與方法……………………………………………………….………..13 第一節 分子生物技術………….…………………………………….…..13 第二節 表現離子通道在爪蟾卵母細胞上……………………………...……13 第三節 電生理紀錄…………………………………...………………………14 第四節 藥物…………………………………………...……………………....15 第五節 實驗數據分析………………………………...…………………........16 第三章 結果………..……………………………………………………………….17 第一節 hERG1 channel 電流特性…………………….……………………...17 第二節 QAs對hERG1 channel外部孔洞的影響…….………………………19 第三節 hERG1 channel在inside-out patch記錄下的特性……….…………..21 第四節 QAs對hERG1 channel內部孔洞的影響………………….…………21 第五節 spermine和鎂離子對hERG1 channel內部孔洞的影響…….……….23 第四章 討論……………………………………………………………….………..26 第一節 hERG1 channel gating之機制……………………………….……….26 第二節 hERG1 channel受外部添加QAs的影響…………………….………27 第三節 hERG1 channel受內部添加QAs、spermine、鎂離子的影響…….…..29 圖次 附圖一 電壓依賴性鉀離子通道家族的tetrameric 6TM architecture……..…33 附圖二 ether-à-go-go gene (EAG) 鉀離子通道家族……………………...…34 附圖三 圖解一個擁有六個α螺旋穿膜片段的hERG1次單元………….…..34 附圖四 ether-à-go-go Related Gene (ERG) K+ Channels電壓依賴特性….....35 圖一 hERG1 channel的生物物理特性…………………………………….36 圖二 hERG1 channel 在P1 pulse較高時的電流變化………………….…37 圖三 hERG1 channel 在不同P1 duration的電流變化…………………....38 圖四 hERG1 channel 在不同P2 pulse下電流變化的情形…………….…39 圖五 hERG1 channel在不同細胞外鉀離子濃度的電流變化………….…40 圖六 QAs對hERG1 channel外部孔洞的影響………………………….…41 圖七 QAs在不同濃度下對hERG1 channel不同P2 pulse的抑制效果…..42 圖八 QAs對hERG1 channel不同P1 duration的抑制效果……………….43 圖九 hERG1 channel在細胞內外鉀離子濃度皆為160mM時的生物物理特性…………………………………………………………………….44 圖十 不同大小的QAs對hERG1 channel內部孔洞的抑制效果……........45 圖十一 QAs在不同濃度下對hERG1 channel內部孔洞的抑制效果……….46 圖十二 hERG1 channel在不同P2 pulse被1μM TPnA-Cl抑制的效果……..47 圖十三 hERG1 channel在不同P1 pulse被1μM TPnA-Cl抑制的效果……..48 圖十四 hERG1 channel被不同濃度spermine抑制的情形…………………..49 圖十五 hERG1 channel在不同P2 pulse被1mM spermine抑制的效果…….50 圖十六 hERG1 channel在不同P1 pulse被1mM spermine抑制的效果…….51 圖十七 hERG1 channel在不同P2 pulse被1mM鎂離子抑制的效果….........52 參考文獻………………………………………………………………………….……53 | |
dc.language.iso | zh-TW | |
dc.title | hERG1鉀離子通道門閥受季銨鹽衍生物調控之機制 | zh_TW |
dc.title | The Effect of Quaternary Ammonium Derivatives
on hERG1 Potassium Channels | en |
dc.type | Thesis | |
dc.date.schoolyear | 100-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 湯志永,黃榮棋,楊雅晴 | |
dc.subject.keyword | hERG1鉀離子通道,季銨鹽衍生物, | zh_TW |
dc.subject.keyword | hERG1 Potassium Channels,Quaternary Ammonium Derivatives, | en |
dc.relation.page | 69 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2012-07-24 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 生理學研究所 | zh_TW |
顯示於系所單位: | 生理學科所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-101-1.pdf 目前未授權公開取用 | 3.06 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。