臺灣博碩士論文加值系統

鈉離子通道是構成細胞膜可興奮性之重要膜蛋白之一。此蛋白可受細胞膜電位變化之激發，啟動一連串形變來控制其門閥開關及活性。一般咸信，構成鈉離子通道的四個結構區域上，各自配備的第四穿膜區段是負責感受電壓以控制門閥的裝置。其中位在第四區域之第四穿膜區段被認為最與通道之不活化反應有關。此區段已被證實可隨膜電位變化而運動。在大鼠腦IIA型鈉離子通道上，我們設計各種點突變於此區段最外側帶電胺基酸之前一個胺基酸上，利用雙電極電壓箝制電生理技術，發現正價突變導致了通道不活化之電壓依賴性與由不活化狀態回復之時間流程均分裂成兩個部分，其中一個部分仍維持著與活化反應間的協同運作，而另一部分則喪失了此種協同。這可能是因為多加一個正電胺基酸於第四穿膜區段上端後，導致當此區段於細胞膜內外運動時，多出一個在能量上亦相當穩定的新的中間位置，因而創造了新的（與活化反應脫聯的）不活化態。而稍微改變此外加正電荷的空間位置，此作用的定量特性即隨之變化，進一步說明了細微的區段位置變化即足以引起不活化狀態的改變。另一方面，中性突變僅單純地使與不活化態相關的、依電壓變化的各種參數在電壓軸上平移，而並未導致新不活化態的形成，亦即影響的僅是第四區段在其原來位置的穩定度。這些發現證明了第四區域第四穿膜區段之運動（或位置）對通道不活化門閥具決定性且極精微的控制。位於此穿膜區段上端的正電胺基酸和與之對應的負電胺基酸之間的靜電交互作用，可能扮演著決定此區段位置進而影響通道不活化狀態的角色。
除了探索鈉通道不活化門閥受電壓控制之分子生理機制外，我們亦進一步研究能調節通道門閥開關之藥物作用機轉。許多在臨床上廣泛使用的抗癲癇藥及局部麻醉藥，對鈉離子通道之抑制作用是與通道被運用的情況有關。抗癲癇藥phenytoin， carbamazepine及 lamotrigine已被證實均選擇(且緩慢地)結合於不活化態，而非靜止態，之鈉離子通道。然而，藥物實際作用的通道構形，藥物受體在通道上的位置，及藥物對不活化態通道的緩慢結合速率之形成因素等重要課題，都尚待解決。Imipramine 具備與carbamazepine完全相同的雙苯環結構以及與許多局部麻醉劑類似的三級胺結構。我們發現imipramine亦選擇結合於鈉離子通道不活化態(解離常數約1.3 μM)甚於靜止態(解離常數大於130 μM)；而且，imipramine及其他結構相似之藥物如carbamazepine及diphenhydramine均可堵住開啟之通道，並以較結合至不活化態更快(imipramine可達近70倍)的結合速率結合至此開啟的、活化態的通道上。 Diclofenac結構上具備與carbamazepine非常相似之雙苯環結構但不具有三級胺長支鏈。我們證明了diclofenac (解離常數約7 μM)可以對鈉離子通道不活化態較carbamazepine (解離常數約25 μM)高之親合力結合至抗癲癇藥之共同受體上。然而，儘管能親合並幫助穩定鈉通道之開啟狀態，在細胞外存在150 mM的鈉離子濃度下，diclofenac並不能如carbamazepine般堵住開啟之通道。但如果細胞外的鈉離子濃度下降或不存在時，diclofenac就能如carbamazepine般堵住通道。因此細胞外鈉離子似可改變diclofenac結合於抗癲癇藥共同受體的三度空間位置。 Diclofenac對鈉通道之親合力隨通道門閥開關狀態而異，解離常數分別是：對靜止態約1500 μM，對活化態約70 μM及對不活化態約7 μM。這些結果指出，抗癲癇藥物受體應位於細胞外之通道孔洞附近(甚或位於其內)，且形成於通道活化時。當通道接著進行不活化反應時，藥物受體亦隨之變化其構形，造成藥物對此不活化態通道較慢之結合速率卻較強之親合力。

The voltage-gated Na+ channel is a crucial membrane protein responding to membrane potential changes by undergoing gating conformational changes, and then controlling the firing pattern in many excitable cells. It is now widely accepted that the S4 segment in each domain of the Na+ channel is the voltage-sensing device for voltage-dependent control of the gating machinery. Among the four S4 segments, the one in domain 4 (S4/D4) is especially implicated in Na+ channel inactivation and has been demonstrated to move externally upon membrane depolarization. We made different point mutations on the residue just external to the outermost charged residue (arginine 1626) in S4/D4 of the rat brain type IIA Na+ channel. Using the two-electrode voltage clamp technique, we found that the inactivation curves as well as the kinetics of recovery from inactivation in the positive-charge mutant channels are split into two components, one happening with and the other without channel activation/deactivation. This is as if the “extra” positive charge above S4/D4 induces new intermediate positions of S4/D4 and consequently new intermediate inactivation states uncoupled from channel activation/deactivation. However, the findings between F1625R and F1625K mutants are qualitatively similar but quantitatively very different, suggesting a significantly different effect on the inactivation gate by a slight difference in the localization of the positive charge. On the other hand, neutral mutations do not induce new inactivation states but shift the voltage dependence of different inactivation parameters in the voltage axis, as if only the relative tendency of S4/D4 to stay in the original outermost and innermost positions is altered. These findings indicate that S4/D4 movement (position) not only decisively but also delicately controls the inactivation gate. Electrostatic interaction between the top charges in S4/D4 and the corresponding counter charges may play an essential role in the determination of S4/D4 position, and therefore the inactivation status of the Na+ channel.
In addition to the exploration of the molecular mechanisms underlying Na+ channel inactivation, we also studied the action of the pharmacological agents capable of modulating the gating process of the channel. Many widely prescribed anticonvulsants and local anesthetics inhibit Na+ channels in a use-dependent fashion, and have been implicated as inactivation stabilizers of the channel. Anticonvulsants phenytoin, carbamazepine, and lamotrigine indeed have all been demonstrated to bind slowly yet selectively to a common receptor site in the inactivated Na+ channels. However, it remains unclear what is the exact gating process that makes the receptor, where the receptor is located, and how the slow drug binding rate (to the inactivated channels) is contrived. Imipramine has a diphenyl structural motif almost identical to that in carbamazepine (a dibenzazepine tricyclic compound), as well as a tertiary amine chain similar to that in many prototypical local anesthetics. We found that imipramine selectively binds to the inactivated (dissociation constant ~1.3 μM) rather than the resting Na+ channels (dissociation constant >130 μM). Moreover, imipramine rapidly blocks open Na+ channels, with a binding rate ~70-fold faster than its binding to the inactivated channels. Similarly, carbamazepine and diphenhydramine are open channel blockers with faster binding rates to the open than to the inactivated channels. Diclofenac contains no tertiary amine chain but a very similar diphenyl motif to carbamazepine and has a use-dependent inhibitory effect similar to the anticonvulsants on Na+ channels. We found that diclofenac binds to the common anticonvulsant receptor with an even smaller dissociation constant (~7 μM) than carbamazepine (~25 μM) in inactivated Na+ channels. However, in the presence of 150 mM external Na+, diclofenac cannot mimic the effect of carbamazepine to block the open channel pore, despite of its significant binding to and stabilization of the open channel. On the other hand, reduction of external Na+ concentration would resume the blocking effect of diclofenac to the open channel pore with a similar binding rate constant to carbamazepine, indicating that external Na+ ions change the binding geometry of diclofenac to the common anticonvulsant receptor in the pore. The binding affinities of diclofenac are different to different gating states of the channel, and are ~1500 μM, ~70 μM, and ~7 μM to resting, activated, and inactivated Na+ channels, respectively. All these data indicate that the anticonvulsant receptor responsible for the use-dependent block of Na+ channels is located at the relatively wide vestibule of external pore mouth and is made suitable for drug binding during channel activation. The receptor, however, continuously changes its conformation in the subsequent gating process, causing the slower drug binding rates yet higher binding affinities to the inactivated Na+ channels.

Contents
Abstract
Abstract in Chinese (中文摘要)
Chapter 1 Introduction
1-1. The basic structural and functional design of the voltage-gated Na+ channel
1-2. The principal gating states of the Na+ channel
1-3. The structural features corresponding to the function of Na+ channels
1-3.1. The pore
1-3.2. The activation gate and the inactivation gate
1-4. Coupling of membrane potential changes to channel gating
1-4.1. Why voltage-dependent?
1-4.2. The voltage sensors
1-4.3. S4 movements
1-4.4. Coupling of S4 movements to the conformational changes that may finally induce gating
1-4.5. The puzzles almost clueless
1-5. The fourth transmembrane segment in domain IV (S4/D4) as the voltage sensor especially relevant to inactivation of Na+ channels
1-6. Pharmacological modulation of Na+ channels gating
1-6.1. The use-dependent inhibition--- a key feature of the anticonvulsant and local anesthetic drugs acting on the Na+ channel
1-6.2. Molecular determinants for selective binding to a common anticonvulsant binding site in inactivated Na+ channels
1-6.3. The exact gating states that the anticonvulsants act on
1-6.3.1. Imipramine and related compounds as inactivation stabilizers and also open channel blockers of Na+ channels: continued conformational change of the drug receptor with membrane depolarization
1-6.3.2 Diclofenac binding to the common anticonvulsant receptor as an open channel stabilizer but not a pore blocker of Na+ channels: locating the drug receptor in the external pore mouth
1-6.4. The possible role of the S3-S4 linker in domain IV of Na+ channels in modulation of the anticonvulsant receptor
Chapter 2 S4/D4 Position Determines Status of the Inactivation Gate in Na+ Channels
Materials and Methods
Results
Discussion
Figures
Chapter 3 Inhibition of Na+ Current by Imipramine and Related Compounds: Different Binding Kinetics as an Inactivation Stabilizer and as an Open Channel Blocker
Materials and Methods
Results
Discussion
Figures
Chapter 4 Diclofenac Binding to the External Pore Mouth of Na+ Channels: a Delicate Gating Modifier and a Protean Open Channel Blocker
Materials and Methods
Results
Discussion
Figures
Concluding Remarks
References

Adler E, Yaari Y, and Selzer ME (1986) Frequency-dependent action of phenytoin on lamprey spinal axons. Brain Res 362: 271-280.
Aggarwal SK, Mackinnon R (1996) Contribution of the S4 segment to gating charge in the Shaker K+ channel. Neuron 16:1169-1177.
Amsterdam, J., Brunswick D, Mendels J (1980) The clinical application of tricyclic antidepressant pharmacokinetics and plasma levels. Am J Psychiat 137:653-663.
Armstrong CM (1981) Sodium channels and gating currents. Physiol Rev 61:644-683.
Armstrong CM (1992) Voltage-dependent ion channels and their gating. Physiol Rev 72:S5-S13.
Armstrong CM, Bezanilla F (1977) Inactivation of the sodium channel. II. Gating current experiments. J Gen Physiol 70:567-590.
Armstrong CM, Bezanilla F, Rojas E (1973) Destruction of sodium conductance inactivation in squid axons perfused with pronase. J Gen Physiol 62:375-391.
Auld VJ, Goldin AL, Krafte DS, Catterall WA, Laster HA, Davidson N, Dunn RJ (1990) A neutral amino acid charge in segment IIS4 dramatically alters the gating properties of the voltage-dependent sodium channel. Proc Natl Acad Sci USA 87:323-327.
Baker, O.S., Larsson, H.P., Mannuzzu, L.M., Isacoff, E.S. (1998). Three transmembrane conformations and sequence-dependent displacement of the S4 domain in Shaker K+ channel gating. Neuron 20,1283-1294.
Balser JR, Nuss HB, Orias DW, Jones DC, Marban E, Tomaselli GF, Lawrence JH (1996) Local anesthetics as effectors of allosteric gating: lidocaine effects on inactivation-deficient rat skeletal muscle Na channels. J Clin Invest 98:2874-2886
Bean BP (1984) Nitrendipine block of cardiac calcium channels: high-affinity binding to the inactivated state. Proc Natl Acad Sci 81:6386-6392.
Bean BP, Cohen CJ, Tsien RW (1983) Lidocaine block of cardiac sodium channels. J Gen Physiol 81:613-642.
Benet LZ, Fie S, Schwartz JB (1996) Design and optimization of dosage regimens: pharmacokinetic data, in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed (Hardman JG, Limbird LE, Molinoff PB and Ruddon RW eds) pp. 1707-1711, p. 1749, McGraw-Hill, New York.
Bennet PB, Valenzuela C, Chen L-Q, Kallen RG (1995) On the molecular nature of the lidocaine receptor of cardiac Na+ channels: modification of block by alterations in the -subunit III-IV interdomain. Circ Res 77:584-592.
Benz I, Kohlhardt M (1992) Differential response of DPI-modified cardiac Na+ channels to antiarrhythmic drugs: no flicker blockade by lidocaine. J Mem Biol 126:257-263.
Bezanilla F (2000) The voltage sensor in voltage dependent ion channels. Physiol Rev 80:555-592.
Bezanilla F, Armstrong CM (1977) Inactivation of the sodium channel. I. Sodium current experiments. J Gen Physiol 70:549-566.
Bolotina V, Courtney KR, Khodorov B (1992) Gate-dependent blockade of sodium channels by phenothiazine derivatives: structure-activity relationships. 42:423-431.
Butterworth JF, Strichartz GR (1990) Molecular mechanisms of local anesthesia: a review. Anesthesiology 72:711-734.
Carruthers SG, Shoeman DW, Hignite CE, Azarnoff DL (1978) Correlation between plasma diphenhydramine level and sedative and antihistamine effects. Clin Pharmacol Ther 23:375-382.
Catterall WA (1984) The molecular basis of neuronal excitability. Science (Wash. DC) 223:653-661.
Catterall WA (1986) Molecular properties of voltage-sensing sodium channels. Annu Rev Biochem 55:953-985.
Catterall WA (1986) Molecular properties of voltage-sensitive sodium channels. Annu Rev Biochem 55:953-985.
Catterall WA (1992) Cellular and molecular biology of voltage-gated sodium channels. Physiol Rev 72:S15-S48.
Chahine M, George AL, Zhou M, Ji S, Sun W, Barchi R, Horn R (1994) Sodium channel mutations in paramyotonia congenita uncouple inactivation from activation. Neuron 12:281-294.
Chahine M, George Jr AL, Zhou M, Ji S, Sun W, Barchi RL, Horn R (1994) Sodium channel mutations in paramyotonia congenita uncouple inactivation from activation. Neuron 12:281-294.
Chen L-Q, Santarelli V, Horn R, Kallen RG (1996) A unique role for the S4 segment of domain 4 in the inactivation of sodium channels. J Gen Physiol 108:549-556.
Clarkson CW, Follmer CH, Ten Eick RE, Hondeghem LM, Yeh JZ (1988) Evidence for two components of sodium channel block by lidocaine in isolated cardiac myocytes. Cir Res 63:869-878.
del Camino D, Yellen G (2001) Tight steric closure at the intracellular activation gate of a voltage-gated K+ channel. Neuron 32:649-656.
Depp MR, Goldin AL (1996) Probing S4-S5 regions of the rat brain sodium channel for the fast inactivation particle receptor site. Biophys J 70: A317.
Ding S, Horn, R (2002) Pivotal role of the tail end of the S6 segment in coupling voltage sensor and activation gate of Shaker K channels. Biophys J 82:174a.
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 280:69-77.
Durell SR, Guy HR (1992) Atomic scale structure and functional models of voltage-gated potassium channels. Biophys J 62:238-250.
Elinder F, Århem P (1999) Role of the individual surface charges of voltage-gated K channels. Biophys J 77:1358-1362.
Elinder F, Århem P, Larsson HP (2001a) Localization of the extracellular end of the voltage sensor S4 in a potassium channel. Biophys J 80:1802-1809.
Elinder F, Mannikko R, Larsson HP (2001b) S4 charges move close to residues in the pore domain during activation in a K+ channel. J Gen Physiol 118:1-10.
Familusi JB (1985) Preliminary Nigerian experience in the use of carbamazepine in children with intractable seizures. Epilepsia 26:10-14
Fleig A, Fitch JM, Goldin AL, Rayner MD, Starkus JG , Ruben PC (1994) Point mutations in IIS4 alter activation and inactivation of rat brain type IIA Na channels in Xenopus oocyte macropatchs. Pflüg Archiv 427:406-413.
Goldin AL, Snutch T, Lubbert H, Dowsett A, Marshall J, Auld V, Downey W, Fritz LC, Lester HA, Dunn R, Catteral WA, Davidson N (1986) Messenger RNA coding for only the α subunit of the rat brain Na+ channel is sufficient for expression of functional channels in Xenopus oocytes. Proc Natl Acad Sci USA 83:7503-7507.
Goldman L, Kenyon JL (1982) Delays in inactivation development and activation kinetics in Myxicola giant axons. J Gen Physiol 80:83-102.
Goldman L, Schauf CL (1972) Inactivation of the sodium current in Myxicola giant axons: evidence for coupling to the activation process. J Gen Physiol 59:659-675.
Guy HR, Seetharamulu P (1986) Molecular model of the action potential sodium channel. Proc Natl Acad Sci USA 83:508-512.
Heinemann SH, Terlau H, Stuhmer W, Imoto K, Numa S (1992) Calcium channel characteristics conferred on the sodium channel by single mutations. Nature 356:441-443.
Hille B (1992) Ionic channels of excitable membranes, Ed. 2. Sinauer Associates, Sunderland, MA.
Hirschberg B, Rovner A, Lieberman M, Patlak J (1995) Transfer of twelve charges is needed to open skeletal muscle Na+ channels. J Gen Physiol 106:1053-1068.
Hodgkin AL, Huxley AF (1952) A quantitative description of membrane current and its application to conductance and excitation in nerve. J Physiol (Cambr) 117:500-544.
Horn R (2000) A new twist in the saga of charge movement in voltage-dependent ion channels. Neuron 25:511-514.
Hoshi T, Zagotta WN, Aldrich RW (1990) Biophysical and molecular mechanisms of Shaker potassium channel inactivation. Science 250: 533-538.
Isacoff EY, Jan YN, Jan LY (1991) Putative receptor for the cytoplasmic inactivation gate in the Shaker K+ channel. Nature 353: 86-90.
Ji S, George AL, Horn R, Barchi RL (1996) Paramyotonia congenita mutations reveal different roles for segments S3 and S4 of domain D4 in hSk M1 sodium channel gating. J Gen Physiol 107:183-194
Jiang Y, Lee A, Chen J, Cadene M, Chait BT, MacKinnon R (2002) Crystal structure and mechanism of a calcium-gated potassium channel. Nature 417:515-522.
Jiang Y, Lee A, Chen J, Ruta V, Cadene M, Chait BT, MacKinnon R (2003) X-ray structure of a voltage-dependent K+ channel. Nature 423:33-41.
Kellenberger S, West JW, Catterall WA, Scheuer T (1997) Molecular analysis of potential hinge residues in the inactivation gate of brain type IIA Na+ channels. J Gen Physiol 109:607-617.
Keynes RD, Elinder F (1999) The crew-helical voltage gating of ion channels. Pro Soc Lond B Biol Sci 266:843-852.
Kondratiev A, Hahin R (2001) ED50 GNa block predictions for phenyl substituted and unsubstituted n-alkanols. J Mem Biol 180:123-136
Kontis KJ, Rounaghi A, Goldin AL (1997) Sodium channel activation gating is affected by substitutions of voltage sensor positive charges in all four domains. J Gen Physiol 110:391-401.
Kühn FJP, Greeff NG (1999) Movement of voltage sensor S4 in domain 4 is tightly coupled to sodium channel fast inactivation and gating charge immobilization. J Gen Physiol 114:167-183.
Kuo C-C, Bean BP (1994a) Sodium channels must deactivate to recovery from inactivation. Neuron 12:819-829.
Kuo C-C, Bean BP (1994b) Slow binding of phenytoin to inactivated sodium channels in rat hippocampal neurons. Mol Pharmacol 46:716-725.
Kuo C-C, Lu L (1997) Characterization of lamotrigine inhibition of Na+ channels in rat hippocampal neurons. Br J Pharmacol 121:1231-1238
Kuo C-C, Chen R-S, Lu L, Chen RC (1997) Carbamazepine inhibition of neyronal Na+ channels: quantitative distinction from phenytoin and possible therapeautic implications. Mol Pharmacol 51:1077-1083
Kuo C-C (1998a) A common anticonvulsant binding site for phenytoin, carbamazepine, and lamotrigine in neuronal Na+ channels. Mol Pharmacol 54:712-721
Kuo C-C (1998b) Imipramine inhibition of transient K+ current: An external open channel blocker preventing fast inactivation. Biophys J 12:2845-2857
Kuo C-C, Huang R-C, Lou B-S (2000) Inhibition of Na+ current by diphenhydramine and other diphenyl compounds: molecular determinants of selective binding to the inactivated channels. Mol Pharmacol 57:135-143
Kuo C-C, 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, Yang S (2001) Recovery from inactivation of T-type Ca2+ channels in rat thalamic neurons. J Neurosci 21(6):1884-1892.
Kuo C-C, Lin T-J, Hsieh C-P (2002) Effect of Na+ flow on Cd2+ block of tetradotoxin-resistant Na+ channels. J Gen Physiol 120:159-172.
Larsson HP (2002) The search is on for the voltage sensor-to-gate coupling. J Gen Physiol 120:475-481.
Larsson HP, Elinder F (2000) A conserved glutamate is important for slow inactivation in K+ channels. Neuron 27:573-583.
Lawrence JH, Orias DW, Balser JR, Nuss HB, Tomaselli GF, O'Rourke B, Marban E (1996) Single-channel analysis of inactivation-defective rat skeletal muscle sodium channel containing the F1304Q mutation. Biophys J 71:1285-1294
Lecar H, Larsson HP (1997) Theory of S4 motion in voltage-gated channels. Biophys J 72:341a.
Lerche H, Peter W, Fleischhauer R, Pika-Hartlaub U, Malina T, Mitrovic N, Lehmann-Horn F (1997) Role in fats inactivation of the IV/S4-S5 loop of the human muscle Na+ channel probed by cysteine mutagenesis. J Physiol (Camb) 505: 345-352
Li H-L, Galue A, Meadows L, Ragsdale DS (1999) A molecular basis for the different local anesthetic affinities of resting versus open and inactivated states of the sodium channel. Mol Pharmacol 55:134-141.
Lipicky RJ, Gilbert DJ, Stillman IM (1972) Diphenylhydantoin inhibition of sodium conductance in squid giant axon. Proc Nalt Acad Sci USA 69: 1758-1760.
Li-Smerin YY, Hackos DH, Swartz KJ (2000) A localized interaction surface for voltage-sensing domains on the pore domain of a K+ channel. Neuron 25:411-423.
Lu Z, Klem AM, Ramu Y (2001) Ion conduction pore is conserved among potassium channels. Nature 413:809-813.
Matsubara T, Clarkson C, Hondeghem L (1987) Lidocaine blocks open and inactivated cardiac sodium channels. Naunyn-Schmiedeberg's Arch Pharmacol 336:224-231
Matsuki N, Quandt FN, Ten Eick RE, Yeh JZ (1984). Characterization of the block of sodium channels by phenytoin in mouse neuroblastoma cells. J Pharmacol Exp Ther 228:523-530.
Matsuki N, Quandt FN, Ten Eick RE, Yeh JZ (1984) Characterization of the block of sodium channels by phenytoin in mouse neuroblastoma cells. J Pharmacol Exp Ther 228:523-530.
McCormack K, Tanouye MA, Iverson LE, Lin J-W, Ramaswami M, McCormack T, Campanelli JT, Mathew MK, Rudy B (1991) A role for hydrophobic residues in the voltage-dependent gating of Shaker K+ channels. Proc Natl Acad Sci USA 88:2931-2935.
McLean MJ, McDonald RL (1983) Multiple actions of phenytoin on mouse spinal cord neurons in cell culture. J Pharmacol Exp Ther 227: 779-789
McLean MJ, McDonald RL (1986) Carbamazepine and 10,11-epoxycarbamazepine produce use- and voltage-dependent limitation of rapidly firing action potentials of mouse central neurons in cell culture. J Pharmacol Exp Ther 238:727-738
McPhee JC, Ragsdale DS, Scheuer T, Catterall WA (1995) A critical role for transmembrane segment IVS6 of the sodium channel α-subunit in fast inactivation. J Biol Chem 270:12025-12034.
McPhee JC, Ragsdale DS, Scheuer T, Catterall WA (1998) A critical role for the S4-S5 intracellular loop in domain IV of the sodium channel α-subunit in fast inactivation. J Biol Chem 273:1121-1129.
Nguyen TP, Horn R (2002) Movement and crevices around a sodium channel S3 segment. J Gen Physiol 120:419-436.
Noda M, Numa S (1987) Structure and function of sodium channels. J Receptor Res 7:467-497.
Noda M, Ikeda T, Suzuki H, Takeshima H, Takahashi T, Kuno M, Numa S (1986) Expression of functional channels from cloned cDNA sequence. Nature (Lond.) 312:826-828.
Nuss HB, Balser JR, Orias DW, Lawrence JH, Tomaselli GF, Marban E (1996) Coupling between fast and slow inactivation revealed by analysis of a point mutation (F1304Q) in m1 rat skeletal muscle sodium channels. J Physiol 494:411-429
O’leary ME, Chen L-Q, Kallen RG, Horn R (1995) A molecular link between activation and inactivation of sodium channels. J Gen Physiol 106: 641-658.
Ogata N, Narahashi T (1989) Block of sodium channels by psychtropic drugs in single guinea-pig cardiac myocytes. Br J Pharmacol 97:905-913
Papazian DM, Shao XM, Seoh S-A, Mock AF, Huang Y, Wainstock DH (1995) Electrostatic interactions of S4 voltage sensor in Shaker K+ channels. Neuron 14:1293-1301.
Patton DE, Isom LL, Catterall WA, Goldin AL (1994) The adult rat brain 1 subunit modifies activation and inactivation gating of multiple sodium channel  subunit. J Biol Chem 269:17649-17655.
Perozo E, Cortes DM, Cuello LG (1999) Structural arrangements underlying K+ channel activation gating. Science 285:73-78.
Qu Y, Rogers JC, Chen S-F, McCormick KA, Scheuer T, Catterall WA (1999) Functional roles of the extracellular segments of the sodium channel α subunit in voltage-dependent gating and modulation by β1 subunits. J Biol Chem 274:32647-32654.
Quandt FN (1988) Modification of slow inactivation of single sodium channels by phenytoin in neuroblsatoma cells. Mol Pharmacol 34:557-565.
Ragsdale DS, Mcphee JC, Scheuer T, Catterall WA (1994) Molecular determinants of state-dependent block of Na+ channels by local anesthetics. Science 265:1724-1728.
Ragsdale DS, Mcphee JC, Scheuer T, Catterall WA (1996) Common molecular determinants of local anesthetic, antiarrythmic, and anticonvulsant block of voltage gated Na+ channels. Proc Natl Acad Sci USA 93:9270-9275.
Ravindran A, Schild L, Moczydlowski E (1991) Divalent cation selectivity for external block of voltage-dependent Na+ channels prolonged by Batrachotoxin: Zn2+ induces discrete substates in cardiac Na channels. J Gen Physiol 97:89-115.
Rojas E, Armstrong CM (1971) Sodium conductance activation without inactivation in pronase-perfused axons. Nature (Lond.) 229:177-178.
Schain RJ, Ward JW and Guthrie D (1977) Carbamazepine as an anticonvulsant in children. Neurology 27:476-480
Schauf CL, Pencek TL, Davis FA (1976) Slow sodium channel inactivation in Myxicola axons: evidence for a second inactivated state. Biophys J 16:772-778
Schwartz JR, Grigat G (1989) Phenytoin and Carbamazepine: potential and frequency-dependent block of Na+ currents in mammalian myelinated nerve fibers. Epilepsia 30:286-294
Seoh SA, Sigg D, Papazian DM, Bezanilla F (1996) Voltage-sensing residues in the S2 and S4 segments of the Shaker K+ channels. Neuron 16:1159-1167.
Sheets MF, Kyle JW, Kallen RG, Hanck DA (1999) The Na channel voltage sensor associated with inactivation is localized to the external charged residues of domain IV, S4. Biophy J 77:747-757.
Stühmer W, Conti F, Suzuki H, Wang XD, Noda M, Yahagi N, Kubo H, Numa S (1989) Structural parts involved in activation and inactivation of the sodium channel. Nature (Lond) 339:597-603.
Teresa Perez-Garcia M, Chiamvimonvat N, Ranjan R, Balser jr, Tomaselli DF, Marban E (1997) M echanisms of sodium/calcium selectivity in sodium channels probed by cystein mutagenesis and sulfhydryl modification. Biophys J 72:989-996
Tiwari-Woodruff, S.K., Lin M.-c. A., Schulteis, C.T., Papazian, D.M. (2000). Voltage-dependent structure interactions in the Shaker K+ channel. J Gen Physiol 115, 123-138.
Tiwari-Woodruff, S.K., Schulteis, C.T., Mock AF, Papazian D.M. (1997) Electrostatic interactions between transmembrane segments mediate folding of Shaker channel subunits. Biophys. J. 72:1489-1500.
Tomaselli GF, Chiamvimonvat N, Nuss HB, Balser JR, Perez-Garcia MT, Xu RH, Orias DW, Backx PH, Marban E (1995) A mutation in the pore of the sodium channel alters gating. Biophys J 68:1814-1827 .
Tristani-Firouzi M, Chen J, Sanguinetti MC (2002) Interactions between S4-S5 linker and S6 transmembrane domain mkodulate gating of HERG K+ channels, J boil Chem 277:18994-19000.
Vedantham V, Cannon SC (1999) The position of the fast-inactivation gate during lidocaine block of voltage-gated Na+ channels. J Gen Physiol 113:7-16.
West JW, Patton DE, Scheuer T, Wang Y, Goldin AL, Catteral WA (1992) A cluster of hydrophobic amino acid residues required for fast Na+ channel inactivation. Proc Natl Acad Sci USA 89:10910-10914.
Willow M, Gonoi T, Catteral WA (1985) Voltage clamp analysis of the inhibitory actions of diphenylhydantoin and carbamazepine on voltage-sensitive sodium channels in neuroblastoma cells. Mol Pharmacol 27:549-558.
Xie XM, Lancaster B, Peakman T, Garthwaite J (1995) Interaction of the antiepileptic drug lamotrigine with recombinant rat brain type IIA Na+ channels and with native Na+ channels in rat hippocampal neurons. Pflugers Arch - Eur J Physiol 430:437-446.
Yang N, George Jr AL, Horn R (1996) Molecular basis of charge movement in voltage-gated sodium channels. Neuron 16:113-122.
Yang N, George Jr AL, Horn R (1997) Probing the outer vestibule of a sodium channel voltage sensor. Biophys J 73:2260-2268.
Yang N, Horn R (1995) Evidence for voltage-dependent S4 movement in sodium channels. Neuron 15:213-218.
Yang Y-C, 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. Mol Pharmacol 62:1228-1237.
Yarov-Yarovoy V, Brown J, Sharp EM, Clare JJ, Scheuer T, Catterall WA (2001) Molecular determinants of voltage-dependent gating and binding of pore-blocking drugs in transmembrane segment IIIS6 of the Na+ channel a subunit. J Biol Chem 276:20-27
Yellen G (1998) The moving parts of voltage-gated ion channels. Q Res Biophys 31:239-295.
Zagotta WN, Hoshi T, Aldrich RW (1990) Restoration of inactivation in mutant Shaker potassium channels by a peptide from ShB. Science 250: 568-571.
Zhou M, Morais-Cabral JH, Mann S, MacKinnon R (2001) Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors. Nature 411:657-661.
Zimmerman JJ, Feldman S (1989) Physical-Chemical properties and biological activity, in Principles of Medicinal Chemistry. 3rd ed (Foye WO ed) pp 7-37, Lea & Febiger, Malvern, PA.