請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/37356
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 劉宏輝 | |
dc.contributor.author | Chien-Hsing Lee | en |
dc.contributor.author | 李建興 | zh_TW |
dc.date.accessioned | 2021-06-13T15:25:24Z | - |
dc.date.available | 2013-09-11 | |
dc.date.copyright | 2008-09-11 | |
dc.date.issued | 2008 | |
dc.date.submitted | 2008-07-18 | |
dc.identifier.citation | Abraham, MR, Jahangir, A, Alekseev, AE, Terzic, A (1999) Channelopathies of inwardly rectifying potassium channels. FASEB J 13(14): 1901-1910.
Angehagen, M, Ronnback, L, Hansson, E, Ben-Menachem, E (2005) Topiramate reduces AMPA-induced Ca2+ transients and inhibits GluR1 subunit phosphorylation in astrocytes from primary cultures. J Neurochem 94(4): 1124-1130. Ankorina-Stark, I, Haxelmans, S, Schlatter, E (1997) Receptors for bradykinin and prostaglandin E2 coupled to Ca2+ signalling in rat cortical collecting duct. Cell Calcium 22(4): 269-275. Antcliff, JF, Haider, S, Proks, P, Sansom, MS, Ashcroft, FM (2005). Functional analysis of a structural model of the ATP-binding site of the KATP channel Kir6.2 subunit. EMBO J 24 (2): 229-239. Ashcroft, FM, Gribble, FM (1998) Correlating structure and function in ATP-sensitive K+ channels. Trends Neurosci 21(7): 288-294. Babilonia, E, Wei, Y, Sterling, H, Kaminski, P, Wolin, M, Wang, WH (2005) Superoxide anions are involved in mediating the effect of low K intake on c-Src expression and renal K secretion in the cortical collecting duct. J Biol Chem 280(11): 10790-10796. Baukrowitz, T, Schulte, U, Oliver, D, Herlitze, S, Krauter, T, Tucker, SJ, Ruppersberg, JP, Fakler, B. (1998). PIP2 and PIP as determinants for ATP inhibition of KATP channels. Science, 282(5391): 1141-4. Beguin, P, Nagashima, K, Nishimura, M, Gonoi, T, Seino, S (1999) PKA-mediated phosphorylation of the human KATP channel: separate roles of Kir6.2 and SUR1 subunit phosphorylation. EMBO J 18(17): 4722-4732. Bertrand, S, Nouel, D, Morin, F, Nagy, F, Lacaille, JC (2003) Gabapentin actions on Kir3 currents and N-type Ca2+ channels via GABAB receptors in hippocampal pyramidal cells. Synapse 50(2): 95-109. Bichet, D, Haass, FA, Jan, LY (2003) Merging functional studies with structures of inward-rectifier K+ channels. Nat Rev Neurosci 4(12): 957-967. Boim, MA, Ho, K, Shuck, ME, Bienkowski, MJ, Block, JH, Slightom, JL, Yang, Y, Brenner, BM, Hebert, SC (1995) ROMK inwardly rectifying ATP-sensitive K+ channel. II. Cloning and distribution of alternative forms. Am J Physiol 268(6 Pt 2): F1132-1140. Capener, CE, Proks, P, Ashcroft, FM, Sansom, MS (2003) Filter flexibility in a mammalian K channel: models and simulations of Kir6.2 mutants. Choe, H, Zhou, H, Palmer, LG, Sackin, H (1997) A conserved cytoplasmic region of ROMK modulates pH sensitivity, conductance, and gating. Am J Physiol 273(4 Pt 2): F516-529. Doyle, DA, Morais Cabral, J, Pfuetzner, RA, Kuo, A, Gulbis, JM, Cohen, SL, Chait, BT, MacKinnon, R (1998) The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280(5360): 69-77. Du, X, Zhang, H, Lopes, C, Mirshahi, T, Rohacs, T, Logothetis, DE (2004) Characteristic interactions with phosphatidylinositol 4,5-bisphosphate determine regulation of kir channels by diverse modulators. J Biol Chem 279(36): 37271-37281. Dudek, FE, Sutula, TP (2007) Epileptogenesis in the dentate gyrus: a critical perspective. Prog Brain Res 163: 755-773. Dulhanty, AM, Riordan, JR (1994) Phosphorylation by cAMP-dependent protein kinase causes a conformational change in the R domain of the cystic fibrosis transmembrane conductance regulator. Biochemistry 33(13):4072-4079. Eckstein, F (1985) Nucleoside phosphorothioates. Annu Rev Biochem 54: 367-402. Ellena, JF, Moulthrop, J, Wu, J, Rauch, M, Jaysinghne, S, Castle, JD, Cafiso, DS (2004) Membrane position of a basic aromatic peptide that sequesters phosphatidylinositol 4,5 bisphosphate determined by site-directed spin labeling and high-resolution NMR. Biophys J 87(5): 3221-3233. Espinoza-Fonseca, LM, Kast, D, Thomas, DD (2007) Molecular dynamics simulations reveal a disorder-to-order transition on phosphorylation of smooth muscle myosin. Biophys J 93(6): 2083-2090. Fakler, B, Schultz, JH, Yang, J, Schulte, U, Brandle, U, Zenner, HP, Jan, LY, Ruppersberg, JP (1996) Identification of a titratable lysine residue that determines sensitivity of kidney potassium channels (ROMK) to intracellular pH. EMBO J 15(16): 4093-4099. Faraldo-Gomez, JD, Forrest, LR, Baaden, M, Bond, PJ, Domene, C, Patargias, G, Cuthbertson, J, Sansom, MS (2004) Conformational sampling and dynamics of membrane proteins from 10-nanosecond computer simulations. Proteins 57(4): 783-791. Ford, MG, Pearse, BM, Higgins, MK, Vallis, Y, Owen, DJ, Gibson, A, Hopkins, CR, Evans, PR, McMahon, HT (2001) Simultaneous binding of PtdIns(4,5)P2 and clathrin by AP180 in the nucleation of clathrin lattices on membranes. Science 291(5506): 1051-1055. Freiman, TM, Kukolja, J, Heinemeyer, J, Eckhardt, K, Aranda, H, Rominger, A, Dooley, DJ, Zentner, J, Feuerstein, TJ (2001) Modulation of K+-evoked [3H]-noradrenaline release from rat and human brain slices by gabapentin: involvement of KATP channels. Naunyn Schmiedebergs Arch Pharmacol 363(5): 537-542. Fu, J, Ji, HL, Naren, AP, Kirk, KL (2001) A cluster of negative charges at the amino terminal tail of CFTR regulates ATP-dependent channel gating. J Physiol 536(Pt 2): 459-470. Giebisch, GH (2002) A trail of research on potassium. Kidney Int 62(5):1498-1512. Haider, S, Grottesi, A, Hall, BA, Ashcroft, FM, Sansom, MS (2005) Conformational dynamics of the ligand-binding domain of inward rectifier K channels as revealed by molecular dynamics simulations: toward an understanding of Kir channel gating. Biophys J 88(5): 3310-3320. Haider, S, Khalid, S, Tucker, SJ, Ashcroft, FM, Sansom, MS (2007) Molecular dynamics simulations of inwardly rectifying (Kir) potassium channels: a comparative study. Biochemistry 46(12): 3643-3652. Hebert, SC (1998) Roles of Na-K-2Cl and Na-Cl cotransporters and ROMK potassium channels in urinary concentrating mechanism. Am J Physiol 275(3 Pt 2): F325-327. Hebert, SC (2003) Bartter syndrome. Curr Opin Nephrol Hypertens 12(5): 527-532. Hebert, SC, Desir, G, Giebisch, G, Wang, W (2005) Molecular diversity and regulation of renal potassium channels. Physiol Rev 85(1): 319-371. Hilgemann, DW, Ball, R (1996) Regulation of cardiac Na+,Ca2+ exchange and KATP potassium channels by PIP2. Science 273(5277): 956-959. Ho, K, Nichols, CG, Lederer, WJ, Lytton, J, Vassilev, PM, Kanazirska, MV, Hebert, SC (1993) Cloning and expression of an inwardly rectifying ATP-regulated potassium channel. Nature 362(6415): 31-38. Huang, CL, Feng, S, Hilgemann, DW (1998) Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gbetagamma. Nature 391(6669): 803-806. Huang, CW, Huang, CC, Liu, YC, Wu, SN (2004) Inhibitory effect of lamotrigine on A-type potassium current in hippocampal neuron-derived H19-7 cells. Epilepsia 45(7): 729-736. Huang, CW, Huang, CC, Wu, SN (2007) Activation by zonisamide, a newer antiepileptic drug, of large-conductance calcium-activated potassium channel in differentiated hippocampal neuron-derived H19-7 cells. J Pharmacol Exp Ther 321(1): 98-106. Huang, CW, Huang, CC, Wu, SN (2006) The opening effect of pregabalin on ATP-sensitive potassium channels in differentiated hippocampal neuron-derived H19-7 cells. Epilepsia 47(4): 720-726. Jiang, C, Qu, Z, Xu, H (2002) Gating of inward rectifier K+ channels by proton-mediated interactions of intracellular protein domains. Trends Cardiovasc Med 12(1): 5-13. Judge, SI, Smith, PJ, Stewart, PE, Bever, CT, Jr. (2007) Potassium channel blockers and openers as CNS neurologic therapeutic agents. Recent Patents CNS Drug Discov 2(3): 200-228. Kenna, S, Roper, J, Ho, K, Hebert, S, Ashcroft, SJ, Ashcroft, FM (1994) Differential expression of the inwardly-rectifying K-channel ROMK1 in rat brain. Brain Res Mol Brain Res 24(1-4): 353-356. Kiehn, J, Karle, C, Thomas, D, Yao, X, Brachmann, J, Kubler, W (1998) HERG potassium channel activation is shifted by phorbol esters via protein kinase A-dependent pathways. J Biol Chem 273(39): 25285-25291. Kobayashi, T, Ikeda, K (2006) G protein-activated inwardly rectifying potassium channels as potential therapeutic targets. Curr Pharm Des 12(34): 4513-4523. Kobayashi, T, Ikeda, K, Kumanishi, T (2000) Inhibition by various antipsychotic drugs of the G-protein-activated inwardly rectifying K+ (GIRK) channels expressed in xenopus oocytes. Br J Pharmacol 129(8): 1716-1722. Kobayashi, T, Nishizawa, D, Iwamura, T, Ikeda, K (2007) Inhibition by cocaine of G protein-activated inwardly rectifying K+ channels expressed in Xenopus oocytes. Toxicol In Vitro 21(4): 656-664. Kofuji, P, Newman, EA (2004) Potassium buffering in the central nervous system. Neuroscience 129(4): 1045-1056. Kohda, Y, Ding, W, Phan, E, Housini, I, Wang, J, Star, RA, Huang, CL (1998) Localization of the ROMK potassium channel to the apical membrane of distal nephron in rat kidney. Kidney Int 54(4): 1214-1223. Kubo, Y, Baldwin, TJ, Jan, YN, Jan, LY (1993a) Primary structure and functional expression of a mouse inward rectifier potassium channel. Nature 362(6416): 127-133. Kubo, Y, Reuveny, E, Slesinger, PA, Jan, YN, Jan, LY (1993b) Primary structure and functional expression of a rat G-protein-coupled muscarinic potassium channel. Nature 364(6440): 802-806. Kuo, A, Gulbis, JM, Antcliff, JF, Rahman, T, Lowe, ED, Zimmer, J, Cuthbertson, J, Ashcroft, FM, Ezaki, T, Doyle, DA (2003) Crystal structure of the potassium channel KirBac1.1 in the closed state. Science 300(5627): 1922-1926. Kuzniecky, R, Ho, S, Pan, J, Martin, R, Gilliam, F, Faught, E, Hetherington, H (2002) Modulation of cerebral GABA by topiramate, lamotrigine, and gabapentin in healthy adults. Neurology 58(3): 368-372. Lee, CH, Huang, PT, Lou, KL, Liou, HH (2008) Functional and structural characterization of PKA-mediated pHi gating of ROMK1 channels. J Mol Graph Model (In press) Lee, WS, Hebert, SC (1995) ROMK inwardly rectifying ATP-sensitive K+ channel. I. Expression in rat distal nephron segments. Am J Physiol 268(6 Pt 2): F1124-1131. Leipziger, J, MacGregor, GG, Cooper, GJ, Xu, J, Hebert, SC, Giebisch, G (2000) PKA site mutations of ROMK2 channels shift the pH dependence to more alkaline values. Am J Physiol Renal Physiol 279(5): F919-926. Leung, YM, Zeng, WZ, Liou, HH, Solaro, CR, Huang, CL (2000) Phosphatidylinositol 4,5-bisphosphate and intracellular pH regulate the ROMK1 potassium channel via separate but interrelated mechanisms. J Biol Chem 275(14): 10182-10189. Levitan, IB (1994) Modulation of ion channels by protein phosphorylation and dephosphorylation. Annu Rev Physiol 56: 193-212. Lin, D, Sterling, H, Lerea, KM, Giebisch, G, Wang, WH (2002) Protein kinase C (PKC)-induced phosphorylation of ROMK1 is essential for the surface expression of ROMK1 channels. J Biol Chem 277(46): 44278-44284. Lindberger, M, Luhr, O, Johannessen, SI, Larsson, S, Tomson, T (2003) Serum concentrations and effects of gabapentin and vigabatrin: observations from a dose titration study. Ther Drug Monit 25(4): 457-462. Liou, HH, Zhou, SS, Huang, CL (1999) Regulation of ROMK1 channel by protein kinase A via a phosphatidylinositol 4,5-bisphosphate-dependent mechanism. Proc Natl Acad Sci U S A 96(10): 5820-5825. Lopes, CM, Zhang, H, Rohacs, T, Jin, T, Yang, J, Logothetis, DE (2002) Alterations in conserved Kir channel-PIP2 interactions underlie channelopathies. Neuron 34(6): 933-944. Lu, T, Zhu, YG, Yang, J (1999) Cytoplasmic amino and carboxyl domains form a wide intracellular vestibule in an inwardly rectifying potassium channel. Proc Natl Acad Sci U S A 96(17): 9926-9931. MacGregor, GG, Xu, JZ, McNicholas, CM, Giebisch, G, Hebert, SC (1998) Partially active channels produced by PKA site mutation of the cloned renal K+ channel, ROMK2 (kir1.2). Am J Physiol 275(3 Pt 2): F415-422. Macica, CM, Yang, Y, Lerea, K, Hebert, SC, Wang, W (1998) Role of the NH2 terminus of the cloned renal K+ channel, ROMK1, in arachidonic acid-mediated inhibition. Am J Physiol 274(1 Pt 2): F175-181. Madeja, M, Margineanu, DG, Gorji, A, Siep, E, Boerrigter, P, Klitgaard, H, Speckmann, EJ (2003) Reduction of voltage-operated potassium currents by levetiracetam: a novel antiepileptic mechanism of action? Neuropharmacology 45(5): 661-671. McClelland, D, Evans, RM, Barkworth, L, Martin, DJ, Scott, RH (2004) A study comparing the actions of gabapentin and pregabalin on the electrophysiological properties of cultured DRG neurones from neonatal rats. BMC Pharmacol 2004 4:14. McNicholas, CM, MacGregor, GG, Islas, LD, Yang, Y, Hebert, SC, Giebisch, G (1998) pH-dependent modulation of the cloned renal K+ channel, ROMK. Am J Physiol 275(6 Pt 2): F972-981. Mennitt, PA, Wade, JB, Ecelbarger, CA, Palmer, LG, Frindt, G (1997) Localization of ROMK channels in the rat kidney. J Am Soc Nephrol 8(12): 1823-1830. Minami, K, Gereau, RWt, Minami, M, Heinemann, SF, Harris, RA (1998) Effects of ethanol and anesthetics on type 1 and 5 metabotropic glutamate receptors expressed in Xenopus laevis oocytes. Mol Pharmacol 53(1): 148-156. Mizielinska, SM (2007) Ion channels in epilepsy. Biochem Soc Trans 35(Pt 5): 1077-1079. Murbartian, J, Lei, Q, Sando, JJ, Bayliss, DA (2005) Sequential phosphorylation mediates receptor- and kinase-induced inhibition of TREK-1 background potassium channels. J Biol Chem 280(34): 30175-30184. Nadeau, H, McKinney, S, Anderson, DJ, Lester, HA (2000) ROMK1 (Kir1.1) causes apoptosis and chronic silencing of hippocampal neurons. J Neurophysiol 84(2): 1062-1075. Neusch, C, Weishaupt, JH, Bahr, M (2003) Kir channels in the CNS: emerging new roles and implications for neurological diseases. Cell Tissue Res 311(2): 131-138. Ng, GY, Bertrand, S, Sullivan, R, Ethier, N, Wang, J, Yergey, J, Belley, M, Trimble, L, Bateman, K, Alder, L, Smith, A, McKernan, R, Metters, K, O'Neill, GP, Lacaille, JC, Hebert, TE (2001) Gamma-aminobutyric acid type B receptors with specific heterodimer composition and postsynaptic actions in hippocampal neurons are targets of anticonvulsant gabapentin action. Mol Pharmacol 59(1): 144-152. O'Connell, AD, Leng, Q, Dong, K, MacGregor, GG, Giebisch, G, Hebert, SC (2005) Phosphorylation-regulated endoplasmic reticulum retention signal in the renal outer-medullary K+ channel (ROMK). Proc Natl Acad Sci U S A 102(28): 9954-9959. Perry, PJ, Miller, DD, Arndt, SV, Cadoret, RJ (1991) Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients. Am J Psychiatry 148(2): 231-235. Petit-Jacques, J, Sui, JL, Logothetis, DE (1999) Synergistic activation of G protein-gated inwardly rectifying potassium channels by the betagamma subunits of G proteins and Na+ and Mg2+ ions. J Gen Physiol 114(5): 673-684. Reimann, F, Ashcroft, FM (1999) Inwardly rectifying potassium channels. Curr Opin Cell Biol 11(4): 503-508. Rojas, A, Cui, N, Su, J, Yang, L, Muhumuza, JP, Jiang, C. (2007) Protein kinase C dependent inhibition of the heteromeric Kir4.1-Kir5.1 channel. Biochim Biophys Acta, 1768(9): 2030-2042. Saad, JS, Miller, J, Tai, J, Kim, A, Ghanam, RH, Summers, MF (2006) Structural basis for targeting HIV-1 Gag proteins to the plasma membrane for virus assembly. Proc Natl Acad Sci U S A 103(30): 11364-11369. Sadja, R, Smadja, K, Alagem, N, Reuveny, E (2001) Coupling Gβγ-dependent activation to channel opening via pore elements in inwardly rectifying potassium channels. Neuron 29(3): 669-680. Sharma, AK, Reams, RY, Jordan, WH, Miller, MA, Thacker, HL, Snyder, PW (2007) Mesial temporal lobe epilepsy: pathogenesis, induced rodent models and lesions. Toxicol Pathol 35(7): 984-999. Shuck, ME, Bock, JH, Benjamin, CW, Tsai, TD, Lee, KS, Slightom, JL, Bienkowski, MJ (1994) Cloning and characterization of multiple forms of the human kidney ROM-K potassium channel. J Biol Chem 269(39): 24261-24270. Shyng, SL, Cukras, CA, Harwood, J, Nichols, CG (2000) Structural determinants of PIP2 regulation of inward rectifier KATP channels. J Gen Physiol 116(5): 599-608. Silver, MR, DeCoursey, TE (1990) Intrinsic gating of inward rectifier in bovine pulmonary artery endothelial cells in the presence or absence of internal Mg2+. J Gen Physiol 96(1): 109-133. Takano, M, Kuratomi, S (2003) Regulation of cardiac inwardly rectifying potassium channels by membrane lipid metabolism. Prog Biophys Mol Biol 81(1): 67-79. Thomas, AM, Brown, SG, Leaney, JL, Tinker, A (2006) Differential phosphoinositide binding to components of the G protein-gated K+ channel. J Membr Biol 211(1): 43-53. Thomas, D, Wendt-Nordahl, G, Rockl, 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. J Pharmacol Exp Ther 297(2): 753-761. Vazquez-Lopez, A, Sierra-Paredes, G, Sierra-Marcuno, G (2005) Role of cAMP-dependent protein kinase on acute picrotoxin-induced seizures. Neurochem Res 30(5): 613-618. Voets, T, Droogmans, G, Nilius, B (1996) Membrane currents and the resting membrane potential in cultured bovine pulmonary artery endothelial cells. J Physiol 497 ( Pt 1): 95-107. Wang, WH, Giebisch, G (1991) Dual modulation of renal ATP-sensitive K+ channel by protein kinases A and C. Proc Natl Acad Sci U S A 88(21): 9722-9725. Wang, WH (1995) View of K+ secretion through the apical K channel of cortical collecting duct. Kidney Int 48(4): 1024-1030. Wang, W, Hebert, SC, Giebisch, G (1997) Renal K+ channels: structure and function. Annu Rev Physiol, 59: 413-436. Wang, W, Sackin, H, Giebisch, G (1992) Renal potassium channels and their regulation. Annu Rev Physiol 54: 81-96. Wuttke, TV, Seebohm, G, Bail, S, Maljevic, S, Lerche, H (2005) The new anticonvulsant retigabine favors voltage-dependent opening of the Kv7.2 (KCNQ2) channel by binding to its activation gate. Mol Pharmacol 67(4): 1009-1017. Xiao, YF, Morgan, JP (1998) Cocaine blockade of the acetylcholine-activated muscarinic K+ channel in ferret cardiac myocytes. J Pharmacol Exp Ther 284(1): 10-18. Xie, LH, John, SA, Ribalet, B, Weiss, JN (2007) Activation of inwardly rectifying potassium (Kir) channels by phosphatidylinosital-4,5-bisphosphate (PIP2): interaction with other regulatory ligands. Prog Biophys Mol Biol 94(3): 320-335. Xu, JZ, Hall, AE, Peterson, LN, Bienkowski, MJ, Eessalu, TE, Hebert, SC (1997) Localization of the ROMK protein on apical membranes of rat kidney nephron segments. Am J Physiol 273(5 Pt 2): F739-748. Xu, ZC, Yang, Y, Hebert, SC (1996) Phosphorylation of the ATP-sensitive, inwardly rectifying K+ channel, ROMK, by cyclic AMP-dependent protein kinase. J Biol Chem 271(16): 9313-9319. Yamada, K, Ji, JJ, Yuan, H, Miki, T, Sato, S, Horimoto, N, Shimizu, T, Seino, S, Inagaki, N (2001) Protective role of ATP-sensitive potassium channels in hypoxia-induced generalized seizure. Science 292(5521): 1543-1546. Yang, XF, Weisenfeld, A, Rothman, SM (2007) Prolonged Exposure to Levetiracetam Reveals a Presynaptic Effect on Neurotransmission. Epilepsia 48(10):1861-1869 Yechikhov, S, Morenkov, E, Chulanova, T, Godukhin, O, Shchipakina, T (2001) Involvement of cAMP- and Ca2+/calmodulin-dependent neuronal protein phosphorylation in mechanisms underlying genetic predisposition to audiogenic seizures in rats. Epilepsy Res 46(1): 15-25. Yokoyama, N, Mori, N, Kumashiro, H (1989) Chemical kindling induced by cAMP and transfer to electrical kindling. Brain Res 492(1-2): 158-162. Yoo, D, Flagg, TP, Olsen, O, Raghuram, V, Foskett, JK, Welling, PA (2004) Assembly and trafficking of a multiprotein ROMK (Kir 1.1) channel complex by PDZ interactions. J Biol Chem 279(8): 6863-6873. Zeng, WZ, Li, XJ, Hilgemann, DW, Huang, CL (2003) Protein kinase C inhibits ROMK1 channel activity via a phosphatidylinositol 4,5-bisphosphate-dependent mechanism. J Biol Chem 278(19): 16852-16856. Zeng, WZ, Liou, HH, Krishna, UM, Falck, JR, Huang, CL (2002) Structural determinants and specificities for ROMK1-phosphoinositide interaction. Am J Physiol Renal Physiol 282(5): F826-834. Zhang, H, He, C, Yan, X, Mirshahi, T, Logothetis, DE (1999) Activation of inwardly rectifying K+ channels by distinct PtdIns(4,5)P2 interactions. Nat Cell Biol 1(3): 183–188. Zona, C, Tancredi, V, Longone, P, D'Arcangelo, G, D'Antuono, M, Manfredi, M, Avoli, M (2002) Neocortical potassium currents are enhanced by the antiepileptic drug lamotrigine. Epilepsia 43(7): 685-690. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/37356 | - |
dc.description.abstract | ROMK1鉀離子通道廣泛分佈於體內,調控許多重要的生理功能,包括:維持細胞靜止膜之電位,神經突觸之興奮性,和腎臟鉀離子的運輸。已知PKA的磷酸化過程可以來調控ROMK1鉀離子通道,近年來有研究指出,PKA調控ROMK1鉀離子通道是藉由於PIP2的參與。ROMK1鉀離子通道也被證明會受到細胞內酸鹼值影響,在細胞內酸性pHi值下,引起ROMK1鉀離子通道的關閉,測得ROMK1鉀離子通道的有效酸性解離常數為6.85。在本實驗中,我們利用inside-out電位鉗定的電生理方式,記錄表現在蛙卵上(Xenopous oocytes)的ROMK1鉀離子通道。PKA磷酸化降低離子通道對細胞內酸鹼值的靈敏度,有效酸性解離常數往較酸性數值偏移(~6.58)。由分子動力學模擬結果表示,當ROMK1鉀離子通道受到PKA磷酸化作用,會產生一個穩定的過渡狀態,縮短PKA磷酸化作用位點S219和PIP2結合位點R217之間的距離,使PIP2結合位點K218向細胞膜移動,這樣結構之變化,導致在離子通道上更容易向細胞膜上的PIP2結合。只有當ROMK1鉀離子通道受到PKA磷酸化作用後,PIP2得以劑量依賴性方式重新活化因酸化而引起活性受抑制的通道。這結果意味著PKA次序性地透過通道結構之變化,以利增加通道與PIP2的相互作用,而調控ROMK1鉀離子通道對細胞內酸鹼值的靈敏度。因此,我們提出了PKA磷酸化作用調控離子通道對細胞內酸鹼值的敏感性之分子機制。
已知ROMK1鉀離子通道的活性受到PKC磷酸化作用而抑制。實驗結果發現由PMA活化PKC磷酸化作用,不僅影響通道對細胞內酸鹼值的靈敏度,並且調控PIP2與離子通道的相互作用。ROMK1鉀離子通道具有六個假定的PKC磷酸化作用位點(S4,S183,T191,T193,S201和T234)。而S183已報導不是PKC磷酸化的位點。我們實驗結果發現,PKC磷酸化作用位點突變的離子通道,S4,T191和S201不影響離子通道對細胞內酸鹼值的敏感性及與PIP2的相互作用。T193和T234不僅調控離子通道對細胞內酸鹼值的敏感性,且影響通道與PIP2的相互作用。我們的結論,PKC磷酸化作用位點T193和T234參與調控離子通道對細胞內酸鹼值的靈敏度,且可透過影響離子通道與PIP2相互作用途徑而導致。 透過建立ROMK1 鉀離子通道同源結構,結合單點突變設計和電生理分析方式。我們的結果顯示,一群帶正電荷的氨基酸(R188,R217,和K 218)在一個適當的距離(~13 Å)而形成一個平面,與細胞膜上的PIP2相互作用。在作用平面區域上下的帶正電荷氨基酸(K187和R212A),無法與PIP2相互作用和改變對細胞內酸鹼值的靈敏度。進一步發現,在作用平面區域上的不帶電荷氨基酸(I192,N215,L216,S219 和L220),亦影響ROMK1鉀離子通道與PIP2的相互作用及調控離子通道對細胞內酸鹼值的靈敏度。在內流型整流鉀離子通道上,我們發現高度保有這一群帶正電荷的氨基酸所聚集形成之作用平面區域。 除了探討ROMK1鉀離子通道受磷酸化控制之分子生理機制外,我們也進一步研究影響ROMK1鉀離子通道活性之藥物機轉。ROMK1鉀離子通道密集分布於海馬迴,具有穩定膜電位的功能。鉀離子通道活性已證實受到許多在臨床上廣泛使用的抗癲癇用藥調控。然而,新一代抗癲癇藥物gabapentin,pregabalin及levetiracetam是否與ROMK1鉀離子通道作用機轉尚未瞭解。我們研究證明這些新一代抗癲癇藥物以dose-dependent 方式活化ROMK1 鉀離子通道。活化機轉是與細胞內pH值及PIP2調節無關,而受到PKA磷酸化之調控。 | zh_TW |
dc.description.abstract | ROMK1 (Kir1.1) channels are widely distributed in different tissues and regulate many important cellular processes, including the membrane resting potentials, cell and synaptic excitability, and the renal K+ transport. ROMK1 channels are mediated by intracellular pH (pHi), phosphorylation by kinases (PKA and PKC) and phosphatidylinositol 4, 5-bisphosphate (PIP2).
Part 1: The regulatory mechanism of ROMK1 channels. We investigate the role of protein kinase A (PKA) in the pHi gating of ROMK1 channels. Using giant patch clamp with Xenopus oocytes expresses wild-type and mutant ROMK1 channels. We investigated between the role of PKA in regulation of ROMK1 channels by pHi and the mechanisms. PKA-mediated phosphorylation decreased the sensitivity of ROMK1 channels to pHi. Molecular dynamics simulations suggest a stable transition state in which the shortening of distance between S219 and R217 and the movement of K218 towards the membrane after the PKA-phosphorylation, which conformational changes resulted in the PIP2 binding residues more accessible to the membrane-bound PIP2. PIP2 dose-dependently reactivates the acidification-induced rundown channels only when ROMK1 channels have been phosphorylated by PKA. It implies a sequence regulatory mechanism in the pHi gating of ROMK1 channels in which the channel-PIP2 interaction may be enhanced through PKA-mediated phosphorylation. We therefore propose a molecular mechanism of the PKA-mediated phosphorylation in regulating the pHi gating of ROMK1 channels. We investigated the role of PKC in regulation of ROMK1 channels by pHi and the mechanisms. Activation of PKC by phorbol myristate acetate (PMA) on ROMK1 channels not only increases its sensitivity to pHi but also reduces PIP2-channels interactions. ROMK1 channels have been five putative PKC phosphorylation sites, S4 and S201, as well as T191, T193 and T234. T193 and T234 are the two main PKC phosphorylation sites that are important for the effect of pHi sensitivity of ROMK1 channels. T193A decreases pHi sensitivity and increases PIP2 interaction with the channels, whereas T193D that mimic the negative charge carried by a phosphate group bound to a serine increases pHi sensitivity. T234A, however, increases pHi sensitivity and reduces PIP2-channels interaction. We conclude that PKC regulates the ROMK1 activity channel to intracellular protons by affecting channel-PIP2 interaction. We perform the experiments in ROMK1 pHi-gating with electrophysiology combined with mutational and structural analysis. The mutants design is based upon previous discoveries regarding the interaction with PIP2 and our present structure model of ROMK1. Our results suggest the importance function of a cluster of basic residues (R188, R217and K218) that form a plane in an appropriate distance (~13 Å) to interact with membrane PIP2. Basic residues (K187 and R212) above and below this plane discriminates on the regulation of this interaction and pHi-gating. Several non basic residues (I192, N215, L216, S219 and L220) in this plane have been found to mediate channel-PIP2 interaction and pHi gating. This plane form by a cluster of basic residues can be observed with high conservation in the Kir channel family. Part 2: we investigated ROMK1 chhannels are modulated by antiepileptic drugs (AEDs) and the mechanisms. Gabapentin (GBP), pregabalin (PGB) and levetiracetam (LEV) are an effective anticonvulsant in treating seizures. We explored the mechanisms underling those AEDs on ROMK1 channels expressed in Xenopus oocytes by an inside-out patch-clamp recording. Those AEDs increased ROMK1 channels activity in a concentration-dependent manner. Those AEDs increases both wide-type and pHi critical residue mutant (K80M) channels activity in different pHi values, indicating that the activatory effect is independent from pHi. Those AEDs does not influence the enhancement effect of channels activity on the wild type is similar to the PIP2-binding sites mutated channels (R188Q, R217A and K218A), suggesting those AEDs may not activate ROMK1 channels through PIP2 pathway. Those AEDs fails to enhance the channel activity in the presence of PKA inhibitor (H89 or KT 5720) indicating that PKA-mediate phosphorylation participates in the function of GBP. This observation is further supported by the evidence that Those AEDs has no effect on the PKA-phosphorylation sites mutated channels (S219A and S313A). Moreover, Those AEDs could not activate the constructed mutants (S219D and S313D) that mimic the negative charge carried by a phosphate group bound to a serine, imply that the effect of PKA in those AEDs may induce conformational modification but not charge-charge interaction in ROMK1 channels. The activity of PKA was increased in epilepsy. ROMK1 channels may be phosphorylated by PKA during seizure which provided an opportunity for those AEDs enhancing ROMK1 channels activity and restore neuronal RMP to prevent seizure spreading. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T15:25:24Z (GMT). No. of bitstreams: 1 ntu-97-D91443003-1.pdf: 5333270 bytes, checksum: 38043a3d94d8fffa19c2504a7cf43219 (MD5) Previous issue date: 2008 | en |
dc.description.tableofcontents | 口試委員會審定書………………………………………………………………………………….ii
誌謝………………………………………………………………………………………………….iii 中文摘要…………………………………………………………………………………………….iv 英文摘要…………………………………………………………………………………………….vi 第一章 緒論………………………………………………………………………………………..01 第一節 內流型整流鉀離子通道………………………………………………………..........02 第二節 腎臟外髓質上的內流型整流鉀離子通道…………………………………………..04 第三節 ROMK1通道受到細胞內因子調控………………………………………………...06 第四節 ROMK1通道與癲癇症……………………………………………………………...14 第五節 研究目的與動機……………………………………………………………………..16 第二章 實驗材料與方法…………………………………………………………………………..20 第三章 研究結果…………………………………………………………………………………..27 第一節PKA磷酸化作用影響ROMK1通道對細胞內酸鹼度的靈敏度…………………..28 第二節PIP2次序性參與PKA影響ROMK1通道對細胞內酸鹼值的靈敏度……………..29 第三節ROMK1通道磷酸化的結構分析…………………………………………………….30 第四節PKC磷酸化影響ROMK1通道對細胞內酸鹼度的靈敏度…………………………30 第五節PIP2參與PKC影響ROMK1通道對細胞內酸鹼值的靈敏度………………………31 第六節 ROMK1通道存有一個PIP2作用平面區域…………………………………………32 第七節 位於作用平面區域上的非正電氨基酸影響ROMK1通道與PIP2作用…………...33 第八節 PIP2作用平面區域高度性地存在內流型整流鉀離子通道………………………...34 第九節Gabapentin(GBP)可增加ROMK1通道之電流………………………………………34 第十節 細胞內酸鹼值不參與GBP與ROMK1通道之交互作用………………………….34 第十一節 PIP2不參與GBP與ROMK1通道之交互作用………………………………….35 第十二節 PKA參與GBP與ROMK1通道之交互作用……………………………………35 第十三節Levetiracetam增加ROMK1通道之電流…………………………………………36 第十四節 細胞內酸鹼值不參與LEV與ROMK1通道之交互作用……………………….37 第十五節 PIP2不參與LEV與ROMK1通道之交互作用………………………………….37 第十六節 PKC不參與LEV與ROMK1通道之交互作用………………………………..38 第十七節 PKA參與LEV與ROMK1通道之交互作用…………………………………..38 第十八節Pregabalin可增加ROMK1通道之電流…………………………………………39 第十九節 細胞內酸鹼值不參與PGB與ROMK1通道之交互作用……………………...40 第二十節 PIP2不參與PGB與ROMK1通道之交互作用………………………………....40 第二十一節 PKC參與PGB與ROMK1通道之交互作用………………………………...40 第二十二節 PKA參與PGB與ROMK1通道之交互作用………………………………...41 第四章 討論………………………………………………………………………………………..43 第五章 結論與未來展望…………………………………………………………………………..55 第六章 圖表………………………………………………………………………………………..57 參考文獻……………………………………………………………………………………………95 著作………………………………………………………………………………………………..108 | |
dc.language.iso | zh-TW | |
dc.title | ROMK1鉀離子通道受磷酸化與抗癲癇藥物調控分子機轉之探討 | zh_TW |
dc.title | Molecular mechanism of ROMK1 channels regulation by phosphorylation and anticonvulsants | en |
dc.type | Thesis | |
dc.date.schoolyear | 96-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 符文美,蘇銘嘉,許桂森,湯志永,樓國隆 | |
dc.subject.keyword | ROMK1鉀離子通道,蛋白激酶,細胞膜脂質,細胞內酸鹼值,抗癲癇用藥, | zh_TW |
dc.subject.keyword | ROMK1 channels,PKA,PKC,PIP2,pHi,antiepileptic drugs, | en |
dc.relation.page | 108 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2008-07-21 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥理學研究所 | zh_TW |
顯示於系所單位: | 藥理學科所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-97-1.pdf 目前未授權公開取用 | 5.21 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。