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OtherIUPHAR Compendium of Voltage-Gated Ion Channels 2005

International Union of Pharmacology. XLVII. Nomenclature and Structure-Function Relationships of Voltage-Gated Sodium Channels

William A. Catterall, Alan L. Goldin and Stephen G. Waxman
Pharmacological Reviews December 2005, 57 (4) 397-409; DOI: https://doi.org/10.1124/pr.57.4.4

Article Figures & Data

Figures

  • Fig. 1.
    Fig. 1.

    Transmembrane organization of sodium channel subunits. The primary structures of the subunits of the voltage-gated ion channels are illustrated as transmembrane-folding diagrams. Cylinders represent probable α-helical segments. Bold lines represent the polypeptide chains of each subunit, with length approximately proportional to the number of amino acid residues in the brain sodium channel subtypes. The extracellular domains of the β1 and β2 subunits are shown as immunoglobulin-like folds. Ψ, sites of probable N-linked glycosylation; P, sites of demonstrated protein phosphorylation by protein kinase A (circles) and protein kinase C (diamonds); shaded, pore-lining S5-P-S6 segments; white circles, the outer (EEDD) and inner (DEKA) rings of amino residues that form the ion selectivity filter and tetrodotoxin binding site; ++, S4 voltage sensors; h in shaded circle, inactivation particle in the inactivation gate loop; open shaded circles, sites implicated in forming the inactivation gate receptor. Sites of binding of α- and β-scorpion toxins and a site of interaction between α and β1 subunits are also shown.

  • Fig. 2.
    Fig. 2.

    Amino acid sequence similarity and phylogenetic relationships of voltage-gated sodium channel α subunits. Phylogenetic relationships by maximum parsimony analysis of rat sodium channel sequences Nav1.1-Nav1.9 and Nax. To perform the analysis, the amino acid sequences for all isoforms were aligned using Clustal W. The amino acid sequences in the alignments were then replaced with the published nucleotide sequences, and the nucleotide sequence alignments were subjected to analysis using the program PAUP*. Divergent portions of the terminal regions and the cytoplasmic loops between domains I-II and II-III were excluded from the PAUP* analysis. The tree was rooted by including the invertebrate sodium channel sequences during the generation of the tree, although these sequences are not shown in the figure.

Tables

  • TABLE 1

    Receptor sites on sodium channels

    Receptor Site Toxin or Drug Domains
    Neurotoxin receptor site 1 Tetrodotoxin IS2–S6, IIS2–S6
    Saxitoxin IIIS2–S6, IVS2–S6
    μ-Conotoxin
    Neurotoxin receptor site 2 Veratridine IS6, IVS6
    Batrachotoxin
    Grayanotoxin
    Neurotoxin receptor site 3 α-Scorpion toxins IS5–IS6, IVS3–S4
    Sea anemone toxins IVS5–S6
    Neurotoxin receptor site 4 β-Scorpion toxins IIS1–S2, IIS3–S4
    Neurotoxin receptor site 5 Brevetoxins IS6, IVS5
    Ciguatoxins
    Neurotoxin receptor site 6 δ-Conotoxins IVS3–S4
    Local anesthetic receptor site Local anesthetic drugs IS6, IIIS6, IVS6
    Antiarrhythmic drugs
    Antiepileptic drugs
  • TABLE 2

    NaV1.1 channels

    Channel name NaV1.1
    Description Voltage-gated sodium channel α subunit
    Other names Brain type I, rat 1, R-I
    Molecular information Human: 2009aa, P35498, X65362, chr. 2q24.3, SCN1A
    Rat: 2009aa, P04775 NM_03975, chr. 3q21
    Mouse: 2048aa, Q68V28, XM_61957, chr. 2
    Associated subunits β1, β2, β3, β4
    Functional assays Voltage-clamp, neurotoxin-activated ion flux, voltage-sensitive dyes
    Current INa
    Conductance Not established
    Ion selectivity Na+ > K+ > Ca2+
    Activation Va = –33 mV1
    Inactivation Vh = –72 mV, th = 0.7 ms at –10 mV1
    Activators Veratridine, batrachotoxin, aconitine, grayanotoxin, and related natural organic toxins; β-scorpion toxins
    Gating modifiers α-Scorpion toxins, sea anemone toxins, and δ-conotoxins, which all slow inactivation
    Blockers Tetrodotoxin (EC50 = 6 nM)1, saxitoxin; local anesthetic, antiepileptic, and antiarrhythmic drugs
    Radioligands [3H]saxitoxin, [3H]batrachotoxin, [125I]scorpion toxins
    Channel distribution Central neurons: primarily localized to cell bodies2; cardiac myocytes3
    Physiological functions Action potential initiation and repetitive firing in neurons; excitation-contraction coupling in cardiac myocytes
    Mutations and pathophysiology Point mutations and deletions cause inherited febrile seizures, GEFS+, and severe myoclonic epilepsy of infancy4,5,6
    Pharmacological significance Site of action of antiepileptic drugs; potential site of side effects of local anesthetics that enter the general circulation or cerebrospinal fluid

    • aa, amino acids; chr., chromosome; GEFS+, generalized epilepsy with febrile seizures plus.

    • ↵1. Clare JJ, Tate SN, Nobbs M, and Romanos MA (2000) Voltage-gated sodium channels as therapeutic targets. Drug Discov Today 5:506-520

    • ↵2. Westenbroek RE, Merrick DK, and Catterall WA (1989) Differential subcellular localization of the RI and RII Na+ channel subtypes in central neurons. Neuron 3:695-704

    • ↵3. Maier SK, Westenbroek RE, Schenkman KA, Feigl EO, Scheuer T, and Catterall WA (2002) An unexpected role for brain-type sodium channels in coupling of cell surface depolarization to contraction in the heart. Proc Natl Acad Sci USA 99:4073-4078

    • ↵4. Escayg A, MacDonald BT, Meisler MH, Baulac S, Huberfeld G, An-Gourfinkel I, Brice A, LeGuern E, Moulard B, Chaigne D, et al. (2000) Mutations ofSCN1A, encoding a neuronal sodium channel, in two families with GEFS + 2. Nat Genet 24:343-345

    • ↵5. Spampanato J, Escayg A, Meisler MH, and Goldin AL (2001) Functional effects of two voltage-gated sodium channel mutations that cause generalized epilepsy with febrile seizures plus type 2. J Neurosci 21:7481-7490

    • ↵6. Nabbout R, Gennaro E, Dalla Bernardina B, Dulac O, Madia F, Bertini E, Capovilla G, Chiron C, Cristofori G, Elia M, et al. (2003) Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy. Neurology 60:1961-1967

  • TABLE 3

    NaV1.2 channels

    Channel name NaV1.2
    Description Voltage-gated sodium channel α subunit
    Other names Brain type II, rat II, R-II
    Molecular information Human: 2005aa, Q99250, X65361, M94055, NM_021007, chr. 2q22-23, SCN2A
    Rat: 2006aa, P04775, X03630, X61149, NM_012647, 3q24
    Mouse: Q68V27, fragment only, chr. 2
    Associated subunits β1, β2, β3, β4
    Functional assays Voltage-clamp, neurotoxin-activated ion flux, voltage-sensitive dyes
    Current INa
    Conductance Not established
    Ion selectivity Na+ > K+ > Ca2+
    Activation Va = –24 mV, τa < 0.4 ms at Va1,2 (see “Comments”)
    Inactivation Vh = –53 mV, τh = 8 ms at Va, th = 0.8 ms at 0 mV1,2
    Activators Veratridine, batrachotoxin, aconitine, grayanotoxin, and related organic toxins; β-scorpion toxins
    Gating modifiers α-Scorpion toxins, sea anemone toxins, and δ-conotoxins, which all slow inactivation
    Blockers Tetrodotoxin (EC50 = 12 nM),3 saxitoxin; local anesthetic, antiepileptic, and antiarrhythmic drugs (EC50 = 11 mM for lidocaine in inactivated state)
    Radioligands [3H]saxitoxin (Kd = 1 nM),5 [3H]batrachotoxin, [125I]α-scorpion toxin (Kd = 2 nM),6 [125I]β-scorpion toxin (Kd = 0.2 nM)7
    Channel distribution Central neurones: primarily localized to unmyelinated and premyelinated axons8,9,10
    Physiological functions Action potential initiation and conduction, repetitive firing
    Mutations and pathophysiology A point mutation has been reported to cause inherited febrile seizures and epilepsy11
    Pharmacological significance Site of action of antiepileptic drugs; probable site of side effects of local anesthetics that reach the general circulation or the cerebrospinal fluid
    Comments Values given for activation and inactivation parameters are for α subunits expressed alone in mammalian cells and measured with an intracellular solution containing aspartate or chloride2 as the primary anion; coexpression of different β subunits gives positive or negative shifts in voltage dependence

    • aa, amino acids; chr., chromosome.

    • ↵1. Mantegazza M, Yu FH, Catterall WA, and Scheuer T (2001) Role of the C-terminal domain in inactivation of brain and cardiac sodium channels. Proc Natl Acad Sci USA 98:15348-15353

    • ↵2. Qu Y, Curtis R, Lawson D, Gilbride K, Ge P, DeStefano PS, Silos-Santiago I, Catterall WA, and Scheuer T (2001) Differential modulation of sodium channel gating and persistent sodium currents by the β1, β2, and β3 subunits. Mol Cell Neurosci 18:570-580

    • ↵3. Noda M, Ikeda T, Kayano T, Suzuki H, Takeshima H, Kurasaki M, Takahashi H, and Numa S (1986) Existence of distinct sodium channel messenger RNAs in rat brain. Nature 320:188-192

    • ↵4. Ragsdale DR, McPhee JC, Scheuer T, and Catterall WA (1996) Common molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated Na+ channels. Proc Natl Acad Sci USA 93:9270-9275

    • ↵5. West JW, Scheuer T, Maechler L, and Catterall WA (1992) Efficient expression of rat brain type IIA Na+ channel α subunits in a somatic cell line. Neuron 8:59-70

    • ↵6. Rogers JC, Qu Y, Tanada TN, Scheuer T, and Catterall WA (1996) Molecular determinants of high affinity binding of α-scorpion toxin and sea anemone toxin in the S3-S4 extracellular loop in domain IV of the Na+ channel α subunit. J Biol Chem 271:15950-15962

    • ↵7. Cestèle S, Qu Y, Rogers JC, Rochat H, Scheuer T, and Catterall, WA (1998) Voltage sensor-trapping: enhanced activation of sodium channels by β-scorpion toxin bound to the S3-S4 loop in domain II. Neuron 21:919-931

    • ↵8. Westenbroek RE, Merrick DK, and Catterall WA (1989) Differential subcellular localization of the RI and RII Na+ channel subtypes in central neurons. Neuron 3:695-704

    • ↵9. Boiko T, Rasband MN, Levinson SR, Caldwell JH, Mandel G, Trimmer JS. and Matthews G. (2001)Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon. Neuron 30:91-104

    • ↵10. Kaplan MR, Cho MH, Ullian EM, Isom LL, Levinson SR, and Barres BA (2001) Differential control of clustering of the sodium channels NaV1.2 and NaV1.6 at developing CNS nodes of Ranvier. Neuron 30:105-119

    • ↵11. Sugawara T, Tsurubuchi Y, Agarwala KL, Ito M, Fukuma G, Mazaki-Miyazaki E, Nagafuji H, Noda M, Imoto K, Wada K, et al. (2001) A missense mutation of the Na+ channel alpha II subunit gene NaV1.2 in a patient with febrile and afebrile seizures causes channel dysfunction. Proc Natl Acad Sci USA 98:6384-6389

  • TABLE 4

    NaV1.3 channels

    Channel name NaV1.3
    Description Voltage-gated sodium channel α subunit
    Other names Brain type 3, rat 3, R-III
    Molecular information Human: 1951aa, Q9NY46, XP0336775, NP008853, chr. 2q23-24, SCN3A
    Rat: 1951aa, P08104, Y00766, NM_012647, chr. 3q24
    Mouse: 2071aa, Q68V26, XM_355332, chr. 2
    Associated subunits β1 and β3 modulate inactivation; time course of expression parallels β31,2
    Functional assays Voltage-clamp, neurotoxin-activated ion flux, voltage-sensitive dyes
    Current INa
    Conductance Not established
    Ion selectivity Na+ > K+ > Ca2+
    Activation Va = –23 to –26 mV3,4
    Inactivation Vh = –65 to –69 mV, τh = 0.8 to 1.5 ms at –10 mV3,4
    Activators Veratridine, batrachotoxin, aconitine, grayanotoxin, and related natural organic toxins; β-scorpion toxins
    Gating modifiers α-Scorpion toxins, sea anemone toxins, and δ-conotoxins, which all slow inactivation
    Blockers Tetrodotoxin (EC50 = 4 nM),1 saxitoxin; local anesthetic, antiepileptic, and antiarrhythmic drugs
    Radioligands [3H]saxitoxin, [3H]batrachotoxin, [125I]scorpion toxins
    Channel distribution Central neurones: primarily expressed in embryonic and early prenatal life; preferentially localized in cell bodies in adult rat brain2,5,6; cardiac myocytes7
    Physiological functions Action potential initiation and conduction; repetitive firing
    Mutations and pathophysiology Not fully established; up-regulated in dorsal root ganglion neurons and dorsal horn neurons in axotomy and other nerve injuries7,8; rapid recovery from inactivation contributes to hyperexcitability following nerve injury10
    Pharmacological significance Site of action of antiepileptic drugs; potential site of side effects of local anesthetics that enter the general circulation or the cerebrospinal fluid

    • aa, amino acids; chr., chromosome.

    • ↵1. Meadows LS, Chen YH, Powell AJ, Clare JJ, and Ragsdale DS (2002) Functional modulation of human NaV1.3 sodium channels expressed in mammalian cells, by auxiliary β1, β2, and β3 subunits. Neuroscience 114:745-753

    • ↵2. Shah BS, Stevens EB, Pinnock RD, Dixon AK, and Lee K (2001) Developmental expression of the novel voltage-gated sodium channel subunit β3 in rat CNS. J Physiol (Lond) 534:763-776

    • ↵3. Chen YH, Dale TJ, Romanos MA, Whitaker WR, Xie XM, and Clare JJ (2000) Cloning, distribution and functional analysis of the type III sodium channel from human brain. Eur J Neurosci 12:4281-4289

    • ↵4. Cummins TR, Aglieco F, Renganathan M, Herzog RI, Dib-Hajj SD, and Waxman SG (2001) NaV1.3 sodium channels: rapid repriming and slow closed-state inactivation display quantitative differences after expression in a mammalian cell line and in spinal sensory neurons. J Neurosci 21:5952-5961

    • ↵5. Beckh S, Noda M, Lübbert H, and Numa S (1989) Differential regulation of three sodium channel messenger RNAs in the rat central nervous system during development. EMBO J 8:3611-3616

    • ↵6. Westenbroek RE, Noebels JL, and Catterall WA (1992) Elevated expression of type II Na+ channels in hypomyelinated axons of shiverer mouse brain. J Neurosci 12:2259-2267

    • ↵7. Maier SK, Westenbroek RE, Schenkman KA, Feigl EO, Scheuer T, and Catterall WA (2002) An unexpected role for brain-type sodium channels in coupling of cell surface depolarization to contraction in the heart, Proc Natl Acad Sci USA 99:4073-4078

    • ↵8. Waxman SG, Kocsis JD, and Black JA (1994) Type III sodium channel mRNA is expressed in embryonic but not adult spinal sensory neurons, and is re-expressed following axotomy. J Neurophysiol 72:466-472

    • ↵9. Hains BC, Saab CY, Klein JP, Craner MC, and Waxman SG (2004) Altered sodium channel expression in second-order spinal sensory neurons contributes to pain after peripheral nerve injury. J Neurosci 24:4832-4840

    • ↵10. Cummins TC and Waxman SG (1997) Down-regulation of tetrodotoxin-resistant sodium currents and up-regulation of a rapidly-repriming tetrodotoxin-sensitive sodium current in spinal sensory neurons following nerve injury. J Neurosci 17:3503-3514

  • TABLE 5

    NaV1.4 channels

    Channel name NaV1.4
    Description Voltage-gated sodium channel α subunit
    Other names SkM1, μ11
    Molecular information Human: 1836aa, M81758, O60217, Q9H3L9,2,3 chr. 17q23-25,3 SCN4A
    Rat: 1840aa, M26643, O706111
    Mouse: 1841aa, AJ278787, Q9ER60,4 chr. 11[64],5 Scn4A
    Associated subunits β1
    Functional assays Voltage-clamp, neurotoxin-activated ion flux, voltage-sensitive dyes
    Current INa
    Conductance 24.9pS human6
    19.8pS rat7
    Ion selectivity Na+ > K+ > Rb+ > Cs (channels reconstituted from rat skeletal muscle sarcolemma)8
    Activation Va = —30 mV (rat α subunit in Xenopus oocytes)9
    Va = —26 mV (human α subunit in CHO cells)10
    Inactivation Vh = —50.1 mV, τh = 0.8 and ∼8 ms at —30 mV, τh = ∼0.3 and ∼3.5 ms at 10 mV (human α subunit in Xenopus oocytes with 200-ms depolarizations using macropatch voltage-clamp)6
    Vh = —56 mV, τh = 1.1 ms at —20 mV (human α subunit in CHO cells with 500-ms depolarizations)10
    Activators Protein: β-scorpion toxins11
    Alkaloids: veratridine,12 batrachotoxin,12 grayanotoxin13
    Gating Modifiers α-Scorpion toxins and sea anemone toxins, which all slow inactivation14
    Blockers Selective: μ-conotoxin GIIIA (EC50 = 19—54 nM in rat,15,16 1.2 μM in human6), μ-conotoxin PIIIA (EC50 = 41 nM in rat16)
    Nonselective: tetrodotoxin (EC50 = 5 nM in rat,1 25 nM in human6), saxitoxin (EC50 = 4.1 nM in rat17)
    Drugs: local anesthetic, antiepileptic, and antiarrhythmic drugs (lidocaine EC50 = 2128 μM in resting state at — 130 mV in rat α subunit, 176 μM in rat αβ1 subunits, 4.4 μM for inactivated state in rat α subunit, 0.9 μM in rat αβ1 subunits18; mexiletine EC50 = 431 μM in resting state at —120 mV in rat αβ1 subunits, 68 μM for inactivated state in rat αβ1 subunits19)
    Radioligands [125I]α scorpion toxin, [3H]batrachotoxin, [3H]saxitoxin, [3H]tetrodotoxin
    Channel distribution High levels in adult skeletal muscle and low levels in neonatal skeletal muscle20
    Physiological functions Action potential initiation and transmission in skeletal muscle
    Mutations and pathophysiology Point mutations in many locations cause hyperkalemic periodic paralysis, paramyotonia congenita, potassium-aggravated myotonias21
    Pharmacological significance Target of local anesthetics used to treat myotonia

    • aa, amino acids; chr., chromosome; CHO, Chinese hamster ovary.

    • ↵1. Trimmer JS, Cooperman SS, Tomiko SA, Zhou J, Crean SM, Boyle MB, Kallen RG, Sheng Z, Barchi RL, Sigworth FJ, et al. (1989) Primary structure and functional expression of a mammalian skeletal muscle sodium channel. Neuron 3:33-49

    • ↵2. George AL Jr, Komisarof J, Kallen RG, and Barchi RL (1992) Primary structure of the adult human skeletal muscle voltage-dependent sodium channel. Ann Neurol 31:131-137

    • ↵3. Wang J, Rojas CV, Zhou J, Schwartz LS, Nicholas H, and Hoffman EP (1992) Sequence and genomic structure of the human adult skeletal muscle sodium channel alpha subunit gene on 17q. Biochem Biophys Res Commun 182:794-801

    • ↵4. Zimmer T, Bollensdorff C, Haufe V, Birch-Hirschfeld E, and Benndorf K (2002) Mouse heart Na+ channels: primary structure and function of two isoforms and alternatively splice variants. Am J Physiol Heart Circ Physiol 282:H1007-H1017

    • ↵5. Ambrose C, Cheng S, Fontaine B, Nadeau JH, MacDonald M, and Gusella JF (1992) The alpha-subunit of the skeletal muscle sodium channel is encoded proximal to Tk-1 on mouse chromosome 11. Mamm Genome 3:151-155

    • ↵6. Chahine M, Bennett PB, George AL Jr, and Horn R (1994) Functional expression and properties of the human skeletal muscle sodium channel. Pflugers Arch Eur J Physiol 427:136-142

    • ↵7. Zhou J, Potts JF, Trimmer JS, Agnew WS, and Sigworth FJ (1991) Multiple gating modes and the effect of modulating factors on the muI sodium channel. Neuron 7:775-785

    • ↵8. Tanaka JC, Eccleston JF, and Barchi RL (1983) Cation selectivity characteristics of the reconstituted voltage-dependent sodium channel purified from rat skeletal muscle sarcolemma. J Biol Chem 258:7519-7526

    • ↵9. Cannon SC, McClatchey AI, and Gusella JF (1993) Modification of the Na+ current conducted by the rat skeletal muscle alpha subunit by co-expression with a human brain beta subunit. Pflugers Arch Eur J Physiol 423:155-157

    • ↵10. Bennett ES (2004) Channel activation voltage alone is directly altered in an isoform-specific manner by Nav1.4 and Nav1.5 cytosplasmic linkers. J Membr Biol 197:155-168

    • ↵11. Marcotte P, Chen L-Q, Kallen RG, and Chahine M (1997) Effects of Tityus serrulatus scorpion toxin gamma on voltage-gated Na+ channels. Circ Res 80:363-369

    • ↵12. Wang S-Y and Wang GK (1998) Point mutations in segment I-S6 render voltage-gated Na+ channels resistant to batrachotoxin. Proc Natl Acad Sci USA 95:2653-2658

    • ↵13. Kimura T, Yamaoka K, Kinoshita E, Maejima H, Yuki T, Yakehiro M, and Seyama I (2001) Novel site on sodium channel α-subunit responsible for the differential sensitivity of grayanotoxin in skeletal and cardiac muscle. Mol Pharmacol 60:865-872

    • ↵14. Chahine M, Plante E, and Kallen RG (1996) Sea anemone toxin (ATX II) modulation of heart and skeletal muscle sodium channel α-subunits expressed in tsA201 cells. J Membr Biol 152:39-48

    • ↵15. Chen L-Q, Chahine M, Kallen RG, and Horn R (1992) Chimeric study of sodium channels from rat skeletal and cardiac muscle. FEBS Lett 309:253-257

    • ↵16. Safo P, Rosenbaum T, Shcherbatko A, Choi D-Y, Han E, Toledo-Aral J, Olivera BM, Brehm P, and Mandel G (2000) Distinction among neuronal subtypes of voltage-activated sodium channels by μ-conotoxin PIIIA. J Neurosci 20:76-80

    • ↵17. Penzotti JL, Lipkind G, Fozzard HA, and Dudley SC Jr (2001) Specific neosaxitoxin interactions with the Na+ channel outer vestibule determined by mutant cycle analysis. Biophys J 80:698-706

    • ↵18. Makielski JC, Limberis J, Fan Z and Kyle JW (1999) Intrinsic lidocaine affinity for Na channels expressed in Xenopus oocytes dependes on α (hH1 vs. rSkM1) and β1 subunits. Cardiovasc Res 42:503-509

    • ↵19. Wang GK, Russell C, and Wang S-Y (2004) Mexiletine block of wild-type and inactivation-deficient human skeletal muscle hNav1.4 Na+ channels. J Physiol (Lond) 554:621-633

    • ↵20. Trimmer JS, Cooperman SS, Agnew WS, and Mandel G (1990) Regulation of muscle sodium channel transcripts during development and in response to denervation. Dev Biol 142:360-367

    • ↵21. Cannon SC (1997) From mutation to myotonia in sodium channel disorders. Neuromuscul Disord 7:241-249

  • TABLE 6

    NaV1.5 channels

    Channel name NaV1.5
    Description Voltage-gated sodium channel α subunit
    Other names h1, skm II, cardiac sodium channel
    Molecular information Human: 2016aa, Q14524, M77235, NM_198056 chr. 2q24, SCN5a
    Rat: 1951aa, P15389, A33996, NM_013125
    Mouse: 2019aa, Q9JJV9, AJ271477, NP067510, chr. 2
    Associated subunits β1, β2, β3, β4
    Functional assays Voltage-clamp, neurotoxin-activated ion flux, voltage-sensitive dyes
    Current INa
    Conductance 19–22pS1
    Ion selectivity Na+ > K+ > Ca2+
    Activation Va = –47 mV, –56 mV with F as the major anion in the intracellular solution2,3
    Va = –27 mV with aspartate as the major anion in the intracellular solution4
    τa = 2.8 ms, 1.6 ms at Va2,4
    Inactivation Vh = –84 mV, –100 mV with F as the major anion in the intracellular solution2,3
    Vh = –61 mV with aspartate as the major anion in the intracellular solution, τh = 1 ms at 0 mV4
    Activators Veratridine, batrachotoxin, aconitine, and related natural organic toxins
    Gating modifiers β-Scorpion toxins, sea anemone toxins, and δ-conotoxins, which all slow inactivation (see “Comments”)
    Blockers Tetrodotoxin (TTX-insensitive, Kd = 1–2 mM),5 saxitoxin; local anesthetic, antiepileptic, and antiarrhythmic drugs (EC50 = 16 mM for lidocaine block of inactivated channels6)
    Radioligands [3H]batrachotoxin (Kd = 25 nM in the presence of α-scorpion toxin)7,8
    Channel distribution Cardiac myocytes,9 immature and denervated skeletal muscle,10 certain brain neurons11
    Physiological functions Action potential initiation and conduction
    Mutations and pathophysiology Point mutations and deletions cause long QT syndrome and idiopathic ventricular fibrillation due to slow and incomplete inactivation of the cardiac sodium current and resulting prolongation of the action potential12
    Pharmacological significance Site of action of antiarrhythmic drugs; site of toxic side effects of local anesthetics that reach the general circulation
    Comments NaV1.5 has lower affinity for α- and β-scorpion toxins than neuronal sodium channels13

    • aa, amino acids; chr., chromosome; TTX, tetrodotoxin.

    • ↵1. Fozzard HA and Hanck, DA (1996) Structure and function of voltage-dependent sodium channels: Comparison of brain II and cardiac isoforms. Physiol Rev 76:887-926

    • ↵2. Sheets MF and Hanck DA (1999) Gating of skeletal and cardiac muscle sodium channels in mammalian cells. J Physiol 514:425-436

    • ↵3. Li RA, Ennis IL, Tomaselli GF, and Marban E (2002) Structural basis of differences in isoform-specific gating and lidocaine block between cardiac and skeletal muscle sodium channels. Mol Pharmacol 61:136-141

    • ↵4. Mantegazza M, Yu FH, Catterall WA, and Scheuer T (2001) Role of the C-terminal domain in inactivation of brain and cardiac sodium channels. Proc Natl Acad Sci USA 98:15348-15353

    • ↵5. Satin J, Kyle JW, Chen M, Bell P, Cribbs LL, Fozzard HA, and Rogart RB (1992) A mutant of TTX-resistant cardiac sodium channels with TTX-sensitive properties Science 256:1202-1205

    • ↵6. Nuss HB, Tomaselli GF, and Marbán E (1995) Cardiac sodium channels (hH1) are intrinsically more sensitive to block by lidocaine than are skeletal muscle (μ1) channels. J Gen Physiol 106:1193-1209

    • ↵7. Sheldon RS, Cannon NJ, and Duff HJ (1986) Binding of [3H]batrachotoxinin A benzoate to specific sites on rat cardiac sodium channels. Mol Pharmacol 30:617-623

    • ↵8. Taouis M, Sheldon RS, Hill RJ, and Duff HJ (1991) Cyclic AMP-dependent regulation of the number of [3H]batrachotoxinin benzoate binding sites on rat cardiac myocytes. J Biol Chem 266:10300-10304

    • ↵9. Rogart RB, Cribbs LL, Muglia LK, Kephart DD, and Kaiser MW (1989) Molecular cloning of a putative tetrodotoxin-resistant rat heart Na+ channel isoform. Proc Natl Acad Sci USA 86:8170-8174

    • ↵10. Kallen RG, Sheng ZH, Yang J, Chen LQ, Rogart RB, and Barchi RL (1990) Primary structure and expression of a sodium channel characteristic of denervated and immature rat skeletal muscle. Neuron 4:233-242

    • ↵11. Hartmann HA, Colom LV, Sutherland ML, and Noebels JL (1999) Selective localization of cardiac SCN5A sodium channels in limbic regions of rat brain. Nat Neurosci 2:593-595

    • ↵12. Keating MT and Sanguinetti MC (2001) Molecular and cellular mechanisms of cardiac arrhythmias. Cell 104:569-580

    • ↵13. Rogers JC, Qu Y, Tanada TN, Scheuer T, and Catterall WA (1996) Molecular determinants of high affinity binding of α-scorpion toxin and sea anemone toxin in the S3-S4 extracellular loop in domain IV of the Na+ channel α subunit. J Biol Chem 271:15950-15962

  • TABLE 7

    NaV1.6 channels

    Channel name NaV1.6
    Description Voltage-gated sodium channel α subunit
    Other names NaCh6,1 PN4,2 CerIII3
    Molecular information Human: 1980aa, O95788, Q9NYX2, A9UQD0, AF050736, AF225988, chr. 12q13,4 SCN8A
    Rat: 1976aa, L39018, AF049239, AF0492401,2
    Mouse: 1976aa, Q60858, AF050736, AF225988,5,6 chr. 15[64],5
    Scn8A
    Associated subunits β1, β2
    Functional assays Voltage-clamp, neurotoxin-activated ion flux, voltage-sensitive dyes
    Current INa
    Conductance Not established
    Ion selectivity Na+
    Activation Va = –8.8 mV (mouse α subunit in Xenopus oocytes with cut-open oocyte voltage-clamp)6
    Va = –17 mV (mouse α subunit with β1 and β2 in Xenopus oocytes with cut-open oocyte voltage-clamp)6
    Va = –26 mV, τa = 0.51 ms and 4.65 ms at –10 mV (mouse α subunit with inactivation removed and β1 and β2 in Xenopus oocytes with cut-open oocyte voltage-clamp)7
    Va = –37.7 mV, τa not determined (rat α subunit in Xenopus oocytes with macropatch voltage-clamp)2,7
    Inactivation Vh = –55 mV, τh = 1.2 and 2.1 ms at –10 mV, τh = 0.98 and 11.6 ms at 10 mV (mouse α subunit in Xenopus oocytes with 500-ms depolarizations using two-electrode voltage-clamp)6
    Vh = –51 mV, τh = 7.1 ms at –20 mV, τh = 0.78 and 8.1 ms at 10 mV (mouse α subunit with β1 and β2 in Xenopus oocytes with 500-ms depolarizations using two-electrode voltage-clamp)6
    Vh = –97.6 mV, τh = 1 ms at –30 mV (rat α subunit in Xenopus oocytes with 5-s depolarizations using macropatch voltage-clamp)2
    Activators Veratridine, batrachotoxin (based on studies with rat brain sodium channels)
    Gating modifiers α-Scorpion toxins and sea anemone toxins, which all slow inactivation8
    Blockers Nonselective: tetrodotoxin (EC50 = 1 nM in rat,2 6 nM in mouse6), saxitoxin; local anesthetic, antiepileptic, and antiarrhythmic drugs
    Radioligands [125I]α-scorpion toxin, [3H]batrachotoxin, [3H]saxitoxin
    [3H]tetrodotoxin (based on studies with rat brain sodium channels)
    Channel distribution Somatodendritic distribution in output neurons of the cerebellum, cerebral cortex, and hippocampus; Purkinje cells in the cerebellar granule cell layer; brainstem and spinal cord, astrocytes, and Schwann cells; DRG; nodes of Ranvier of sensory and motor axons in the PNS; nodes of Ranvier in the CNS1,9,10,11
    Physiological functions Action potential initiation and transmission in central neurons and their myelinated axons; partially responsible for the resurgent and persistent current in cerebellar Purkinje cells12
    Mutations and pathophysiology Point mutation in II S4-S5 causes cerebellar ataxia in jolting mice13; gene disruption causes motor endplate disease in mice5
    Pharmacological significance Potential target for antiepileptic and analgesic drugs

    • aa, amino acids; chr., chromosome; DRG, dorsal root ganglion; PNS, peripheral nerve system; CNS, central nervous system.

    • ↵1. Schaller KL, Krzemien DM, Yarowsky PJ, Krueger BK, and Caldwell JH (1995) A novel, abundant sodium channel expressed in neurons and glia. J Neurosci 15:3231-3242

    • ↵2. Dietrich PS, McGivern JG, Delgado SG, Koch BD, Eglen RM, Hunter JC, and Sangameswaran L (1998) Functional analysis of a voltage-gated sodium channel and its splice variant from rat dorsal root ganglion. J Neurochem 70:2262-2272

    • ↵3. Vega-Saenz de Miera E, Rudy B, Sugimori M, and Llinas R (1997) Molecular characterization of the sodium channel subunits expressed in mammalian cerebellar Purkinje cells. Proc Natl Acad Sci USA 94:7059-7064

    • ↵4. Plummer NW, Galt J, Jones JM, Burgess DL, Sprunger LK, Kohrman DC, and Meisler MH (1998) Exon organization, coding sequence, physical mapping, and polymorphic intragenic markers for the human neuronal sodium channel gene SCN8A. Genomics 54:287-296

    • ↵5. Burgess DL, Kohrman DC, Galt J, Plummer NW, Jones JM, Spear B, and Meisler MH (1995) Mutation of a new sodium channel gene, Scn8a, in the mouse mutant `motor endplate disease'. Nat Genet 10:461-465

    • ↵6. Smith MR, Smith RD, Plummer NW, Meisler MH, and Goldin AL (1998) Functional analysis of the mouse Scn8a sodium channel. J Neurosci 18:6093-6102

    • ↵7. Zhou W and Goldin AL (2004) Use-dependent potentiation of the NaV1.6 sodium channel. Biophys J 87:3862-3872

    • ↵8. Oliveira JS, Redaelli E, Zaharenko AJ, Cassulini RR, Konno K, Pimenta DC, Freitas JC, Clare JJ, and Wanke E (2004) Binding specificity of sea anemone toxins to NaV 1.1–1.6 sodium channels. Unexpected contributions from differences in the IV/S3-S4 outer loop. J Biol Chem 279:33323-33335

    • ↵9. Whitaker W, Faull R, Waldvogel H, Plumpton C, Burbidge S, Emson P, and Clare J (1999) Localization of the type VI voltage-gated sodium channel protein in human CNS. Neuroreport 10:3703-3709

    • ↵10. Tzoumaka E, Tischler AC, Sangameswaran L, Eglen RM, Hunter JC, and Novakovic SD (2000) Differential distribution of the tetrodotoxin-sensitive rPN4/NaCh6/Scn8a sodium channel in the nervous system. J Neurosci Res 60:37-44

    • ↵11. Caldwell JH, Schaller KL, Lasher RS, Peles E, and Levinson SR (2000) Sodium channel NaV1.6 is localized at nodes of Ranvier, dendrites, and synapses. Proc Natl Acad Sci USA 97:5616-5620

    • ↵12. Raman IM, Sprunger LK, Meisler MH, and Bean BP (1997) Altered subthreshold sodium currents and disrupted firing patterns in Purkinje neurons of Scn8a mutant mice. Neuron 19:881-891

    • ↵13. Kohrman DC, Smith MR, Goldin AL, Harris J, and Meisler MH (1996) A missense mutation in the sodium channel Scn8a is responsible for cerebellar ataxia in the mouse mutant jolting. J Neurosci 16:5993-5999

  • TABLE 8

    NaV1.7 channels

    Channel name Nav1.7
    Description Voltage-gated sodium channel α subunit
    Other names PN1,1,2 hNE-Na,3 Nas4
    Molecular information Human: 1977aa, X82835,3 chr. 2q24, SCN9A
    Rat: 1984aa, AF000368, U795681,2
    Mouse: chr. 2[36],5,6 Scn9A
    Associated subunits β1, β2
    Functional assays Voltage-clamp, neurotoxin-activated ion flux, voltage-sensitive dyes
    Current INa
    Conductance 19.5pS (for TTX-sensitive current in DRG neurons)7
    Ion selectivity Na+
    Activation Va = –31 mV (rat α subunit in Xenopus oocytes with macropatch)2
    Va = –45 mV (TTX-sensitive current in DRG neurons)7
    Inactivation Vh = –78 mV, τh = 0.46 and 20 ms at –30 mV, τh = 0.1 and 1.8 ms at 10 mV (rat α subunit in Xenopus oocytes with 10-s depolarizations using two-electrode voltage-clamp)2
    Vh = –60.5 mV (human α subunit in HEK cells with 2-s depolarizations using whole-cell patch clamp)3
    Vh = –39.6 mV (human α subunit with β1 subunit in HEK cells with 2-s depolarizations using whole-cell patch clamp)3
    Vh = –65 mV (TTX-sensitive current in DRG neurons with 50-ms to 1-s depolarizations using whole-cell patch clamp)7
    Activators Veratridine, batrachotoxin (based on studies with rat brain sodium channels)
    Gating modifiers α-Scorpion toxins and sea anemone toxins, which probably slow inactivation based on studies with peripheral nerves and Nav1.28,9
    Blockers Nonselective: tetrodotoxin (EC50 = 4 nM in rat,2 25 nM in human3), saxitoxin; local anesthetic, antiepileptic, and antiarrhythmic drugs (lidocaine EC50 = 450 μM in resting state at –100 mV10)
    Radioligands [125I]α-scorpion toxin, [3H]batrachotoxin, [3H]saxitoxin [3H]tetrodotoxin (based on studies with rat brain sodium channels)
    Channel distribution All types of DRG neurons, sympathetic neurons, Schwann cells, and neuroendocrine cells2,3,11
    Physiological functions Action potential initiation and transmission in peripheral neurons; slow closed-state inactivation facilitates response to slow, small depolarizations12
    Mutations and pathophysiology Mutations (I848T and I858H), observed in inherited erythromelalgia, negatively shift activation, slow deactivation, and enhance response to small depolarizations13,14
    Pharmacological significance Probable target of local anesthetics in the peripheral nervous system

    • aa, amino acids; chr., chromosome; TTX, tetrodotoxin; DRG, dorsal root ganglion; HEK, human embryonic kidney.

    • ↵1. Toledo-Aral JJ, Moss BL, He Z-J, Koszowski G, Whisenand T, Levinson SR, Wolf JJ, Silos-Santiago I, Halegoua S, and Mandel G (1997) Identification of PN1, a predominant voltage-dependent sodium channel expressed principally in peripheral neurons. Proc Natl Acad Sci USA 94:1527-1532

    • ↵2. Sangameswaran L, Fish LM, Koch BD, Rabert DK, Delgado SG, Ilnikca M, Jakeman LB, Novakovic S, Wong K, Sze P, et al. (1997) A novel tetrodotoxin-sensitive, voltage-gated sodium channel expressed in rat and human dorsal root ganglia. J Biol Chem 272:14805-14809

    • ↵3. Klugbauer N, Lacinova L, Flockerzi V, and Hofmann F (1995) Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells. EMBO J 14:1084-1090

    • ↵4. Belcher SM, Zerillo CA, Levenson R, Ritchie JM, and Howe JR (1995) Cloning of a sodium channel α subunit from rabbit Schwann cells. Proc Natl Acad Sci USA 92:11034-11038

    • ↵5. Beckers M-C, Ernst E, Belcher S, Howe J, Levenson R, and Gros P (1996) A new sodium channel α-subunit gene (Scn9a) from Schwann cells maps to the Scn1a, Scn2a, Scn3a cluster of mouse chromosome 2. Genomics 36:202-205

    • ↵6. Kozak CA and Sangameswaran L (1996) Genetic mapping of the peripheral sodium channel genes, Scn9a and Scn10a, in the mouse. Mamm Genome 7:787-792

    • ↵7. Rush AM, Bräu ME, Elliott AA, and Elliott JR (1998) Electrophysiological properties of sodium current subtypes in small cells from adult rat dorsal root ganglia. J Physiol (Lond) 511:771-789

    • ↵8. Cestèle S, Qu Y, Rogers JC, Rochat H, Scheuer T, and Catterall WA (1998) Voltage sensor-trapping: enhanced activation of sodium channels by β-scorpion toxin bound to the S3-S4 loop in domain II. Neuron 21:919-931

    • ↵9. Rogers JC, Qu Y, Tanada TN, Scheuer T, and Catterall WA (1996) Molecular determinants of high affinity binding of α-scorpion toxin and sea anemone toxin in the S3-S4 extracellular loop in domain IV of the Na+ channel α subunit. J Biol Chem 271:15950-15962

    • ↵10. Chevrier P, Vijayaragavan K, and Chahine M (2004) Differential modulation of Nav1.7 and Nav1.8 peripheral nerve sodium channels by the local anesthetic lidocaine. Br J Pharmacol 142:576-584

    • ↵11. Felts PA, Yokoyama S, Dib-Hajj S, Black JA, and Waxman SG (1997) Sodium channel α-subunit mRNAs I, II, III, NaG, Na6 and hNE (PN1): different expression patterns in developing rat nervous system. Mol Brain Res 45:71-82

    • ↵12. Cummins TR, Howe JR, and Waxman SG (1998) Slow closed-state inactivation: a novel mechanism underlying ramp currents in cells expressing the hNE/PN1 sodium channel. J Neurosci 18:9607-9617

    • ↵13. Yang Y, Wang Y, Li S, Xu Z, Li H, Ma I, Fan J, Bu D, Liu B, Fan Z, et al. (2004) Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J Med Genetics 41:171-174

    • ↵14. Cummins TR, Dib-Hajj SD, and Waxman SG (2004) Electrophysiological properties of mutant NaV1.7 sodium channels in a painful inherited neuropathy. J Neurosci 24:8232-8236

  • TABLE 9

    NaV1.8 channels

    Channel name NaV1.8
    Description Voltage-gated sodium channel α subunit
    Other names SNS, PN3
    Molecular information Human: 1957aa, Q9Y5Y9, NM_006514, chr. 3P21-3P24, SCN10A
    Rat: Q63554, Q62968, NM_017247, U53833
    Mouse: P70276, NM_009134, chr. 9
    Associated subunits Not established
    Functional assays Voltage-clamp, voltage-sensitive dyes
    Current ITTX-Rslow
    Conductance Not established
    Ion selectivity Na+
    Activation Threshold = –40 to –30 mV (rat DRG)1,2
    Va = –16 to –21 mV (rat DRG)1,2
    τa = 0.54 ms at –20 mV, 0.36 ms at –10 mV
    Inactivation Vh = ∼–30 mV (rat DRG), τh = 13.5 ms at –20mV, 5.6 ms at –10 mV
    Activators Not established
    Gating modifiers Not established
    Blockers Tetrodotoxin (TTX-resistant, EC50 = 60 mM), lidocaine (and probably other local anesthetics) at high concentrations3
    Radioligands None
    Channel distribution Small and medium-sized DRG neurones and their axons4
    Physiological functions Contributes substantially to the inward current underlying the action potential in DRG neurones5; adds a slowly inactivating sodium current component
    Mutations and pathophysiology Point mutation of Ser356 to an aromatic residue removes TTX resistance6; NaV1.8-null mice exhibit reduced pain responses to noxious mechanical stimuli, delayed development of inflammatory hyperalgesia, and small deficits in noxious thermoreception,7 suggesting a role of Nav1.8 in nociception and in chronic pain; Nav1.8 is up-regulated in some models of inflammatory pain8
    Pharmacological significance Potential target for analgesic drugs
    Comments Rapid recovery from inactivation is conferred by a three-amino acid insert in IVS3–S49; expression is regulated by NGF and GDNF10; insertion of functional Nav1.8 channels in cell membrane is facilitated by annexin II/p1111

    • aa, amino acids; chr., chromosome; TTX, tetrodotoxin; DRG, dorsal root ganglion; NGF, nerve growth factor; GDNF, glial cell-derived growth factor.

    • ↵1. Cummins TR and Waxman SG (1997) Down-regulation of tetrodotoxin-resistant sodium currents and upregulation of a rapidly repriming tetrodotoxin-sensitive sodium current in small spinal sensory neurons after nerve injury. J Neurosci 17:3503-3514

    • ↵2. Sleeper AA, Cummins TR, Hormuzdiar W, Tyrrell L, Dib-Hajj SD, Waxman SG, and Black JA (2000) Changes in expression of two tetrodotoxin-resistant sodium channels and their currents in dorsal root ganglion neurons following sciatic nerve injury, but not rhizotomy. J Neurosci 20:7279-7289

    • ↵3. Akopian AN, Sivilotti L, and Wood JN (1996) A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature 379:257-262

    • ↵4. Djouri L, Fang X, Okuse K, Wood JN, Berry CM, and Lawson SM (2003) The TTX-resistant sodium channel Nav1.8 (SNS/PN3): expression and correlation with membrane properties in rat nociceptive primary afferent neurons. J Physiol (Lond) 550:739-752

    • ↵5. Renganathan M, Cummins TR, and Waxman SG (2001) Contribution of Nav1.8 sodium channels to action potential electrogenesis in DRG neurons. J Neurophysiol 86:629-640

    • ↵6. Sivilotti L, Okuse K, Akopian AN, Moss S, and Wood JN (1997) A single serine residue confers tetrodotoxin insensitivity on the rat sensory-neuron-specific sodium channel SNS. FEBS Lett 409:49-52

    • ↵7. Akopian AN, Souslova V, England S, Okuse K, Ogata N, Ure J, Smith A, Kerr BJ, McMahon SB, Boyce S, et al. (1999) The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat Neurosci 2:541-548

    • ↵8. Tanaka M, Cummins TR, Ishikawa K, Dib-Hajj SD, Black JA, and Waxman SG (1998) SNS Na+ channel expression increases in dorsal root ganglion neurons in the carrageenan inflammatory pain model. Neuroreport 9:967-972

    • ↵9. Dib-Hajj SD, Ishikawa I, Cummins TR, and Waxman SG (1997) Insertion of a SNS-specific tetrapeptide in the S3-S4 linker of D4 accelerates recovery from inactivation of skeletal muscle voltage-gated Na channel μ1 in HEK293 cells. FEBS Lett 416:11-14

    • ↵10. Cummins TR, Black JA, Dib-Hajj SD, and Waxman SG (2000) GDNF up-regulates expression of functional SNS and NaN sodium channels and their currents in axotomized DRG neurons. J Neurosci 20:8754-8761

    • ↵11. Okuse K, Malik-Hall M, Baker MD, Poon W-YL, Kong H, Chao M, and Wood JN (2002) Annexin II light chain regulates sensory neuron-specific sodium channel expression. Nature (Lond) 417:653-656

  • TABLE 10

    NaV1.9 channels

    Channel name NaV1.9
    Description Voltage-gated sodium channel α subunit
    Other names NaN, SNS-2
    Molecular information human: 1792aa, Q9UHE0, AF188679, chr. 3p21-3p24, SCN11A
    Rat: 1765aa, 088457, NM_019265, AJ237852,
    Mouse: 1765aa, Q9R053, NM_011887, chr. 9
    Associated subunits Not established
    Functional assays Voltage clamp
    Current INaTTX-RP
    Conductance Not established
    Ion selectivity Na+
    Activation Threshold = —70 to —60 mV (rat DRG), —80mV (human)
    Va = —47 to —54 mV (rat DRG)1,2,3; τa = 2.93 ms at —60 mV, 4.1 ms at —50 mV, 3.5 ms at —20 mV, and 2.5 ms at —10 mV3
    Inactivation Vh = —44 to —54 mV1,3; τh = 843 ms at —60 mV, 460 ms at —50 mV, 43 ms at —20 mV, and 16 ms at —10 mV3
    Activators Not established
    Gating modifiers Not established
    Blockers Tetrodotoxin (TTX-resistant, EC50 = 40 mM)
    Radioligands None
    Channel distribution c-type DRG neurones, trigeminal neurones and their axons; preferentially expressed in nociceptive DRG neurons4
    Physiological functions Contributes a depolarizing influence to resting potential, amplifies slow subthreshold depolarizations1,3 and modulates excitability of cell membrane5
    Mutations and pathophysiology Preferential expression in c-type dorsal root ganglion neurons suggests a role in nociception
    Pharmacological significance Potential target for analgesic drugs
    Comments Expression is regulated by GDNF6; NaV1.9 current is increased by inflammatory mediators such as PGE27

    • aa, amino acids; chr., chromosome; DRG, dorsal root ganglion; TTX, tetrodotoxin; GDNF, glial cell-derived growth factor; PG, prostaglandin.

    • ↵1. Cummins TR, Dib-Hajj SD, Black JA, Akopian AN, Wood JN, and Waxman SG (1999) A novel persistent tetrodotoxin-resistant sodium current in SNS-null and wild-type small primary sensory neurons. J Neurosci 19:RC43

    • ↵2. Sleeper AA, Cummins TR, Hormuzdiar W, Tyrrell L, Dib-Hajj SD, Waxman SG, and Black JA (2000) Changes in expression of two tetrodotoxin-resistant sodium channels and their currents in dorsal root ganglion neurons following sciatic nerve injury, but not rhizotomy. J Neurosci 20:7279-7289

    • ↵3. Herzog RI, Cummins TR, and Waxman SG (2001) Persistent TTX-resistant Na+ current affects resting potential and response to depolarization in simulated spinal sensory neurons. J Neurophysiol 86:1351-1364

    • ↵4. Fang X, Djouri L, Black JA, Dib-Hajj SD, Waxman SG, and Lawson SN (2002) The presence and role of the TTX-resistant sodium channel NaV1.9 in nociceptive primary afferent neurons. J Neurosci 22:7425-7434

    • ↵5. Baker MD, Chandra SY, Ding Y, Waxman SG, and Wood JN (2003) GTP-induced tetrodotoxin-resistant Na current regulates excitability in mouse and rat small diameter sensory neurones. J Physiol (Lond) 548:373-382

    • ↵6. Cummins TR, Black JA, Dib-Hajj SD, and Waxman SG (2000) GDNF up-regulates expression of functional SNS and NaN sodium channels and their currents in axotomized DRG neurons. J Neurosci 20:8754-8761

    • ↵7. Rush AM and Waxman SG (2004) PGE2 increases the tetrodotoxin-resistant NaV1.9 sodium current in mouse DRG neurons via G-proteins. Brain Res 1023:264-271

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OtherIUPHAR Compendium of Voltage-Gated Ion Channels 2005

International Union of Pharmacology. XLVII. Nomenclature and Structure-Function Relationships of Voltage-Gated Sodium Channels

William A. Catterall, Alan L. Goldin and Stephen G. Waxman
Pharmacological Reviews December 1, 2005, 57 (4) 397-409; DOI: https://doi.org/10.1124/pr.57.4.4
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