![[PDF]](/pb-assets/Icons/adobe-pdf-icon-1498649896243.png){kind=icon}
Abstract
Voltage-gated sodium channels are glycoprotein complexes responsible for initiation and propagation of action potentials in excitable cells such as central and peripheral neurons, cardiac and skeletal muscle myocytes, and neuroendocrine cells. Mammalian sodium channels are heterotrimers, composed of a central, pore-forming α subunit and two auxiliary β subunits. The α subunits form a gene family with at least 10 members. Mutations in α subunit genes have been linked to paroxysmal disorders such as epilepsy, long QT syndrome, and hyperkalemic periodic paralysis in humans, and motor endplate disease and cerebellar ataxia in mice. Three genes encode sodium channel β subunits with at least one alternative splice product. A mutation in the β1 subunit gene has been linked to generalized epilepsy with febrile seizures plus type 1 (GEFS + 1) in a human family with this disease. Sodium channel β subunits are multifunctional. They modulate channel gating and regulate the level of channel expression at the plasma membrane. More recently, they have been shown to function as cell adhesion molecules in terms of interaction with extracellular matrix, regulation of cell migration, cellular aggregation, and interaction with the cytoskeleton. Structure-function studies have resulted in the preliminary assignment of functional domains in the β1 subunit. A sodium channel signaling complex is proposed that involves β subunits as channel modulators as well as cell adhesion molecules, other cell adhesion molecules such as neurofascin and contactin, RPTPβ, and extracellular matrix molecules such as tenascin.
| Ackerman MJ , Clapham DE . 1997. Ion channels-basic science and clinical disease. N Engl J Med 336:1575-1586. Google Scholar, Crossref, Medline, ISI | |
| Adelman JP . 1995. Proteins that interact with the pore-forming subunits of voltage-gated ion channels. Curr Opin Neurobiol 5:286-295. Google Scholar, Crossref, Medline, ISI | |
| An RH , Wang XL , Kerem B , Benhorin J , Medina A , Goldmit M , and others . 1998. Novel LQT-3 mutation affects Na channel activity through interactions between alpha- and beta1-subunits. Circ Res 83:141-146. Google Scholar, Crossref, Medline, ISI | |
| Bieber AJ . 1994. Analysis of cellular adhesion in cultured cells. In: Goldstein L , Fryberg E , editors. Drosophila melanogaster: practical uses in cell biology. Vol. 44. San Diego: Academic Press. p 683-696. Google Scholar | |
| Blackburn-Munro G , Fleetwood-Walker SM . 1999. The sodium channel auxiliary subunits β1 and β2 are differentially expressed in the spinal cord of neuropathic rats. Neuroscience 90:153-164. Google Scholar, Crossref, Medline, ISI | |
| Catterall WA . 1992. Cellular and molecular biology of voltage-gated sodium channels. Physiol Rev 72:S15-S48. Google Scholar, Crossref, Medline, ISI | |
| Catterall WA . 1999. Molecular properties of brain sodium channels: an important target for anticonvulsant drugs. Adv Neurol 79:441-456. Google Scholar, Medline | |
| Catterall WA . 2000. From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron 26:13-25. Google Scholar, Crossref, Medline, ISI | |
| Chauhan VS , Tuvia S , Buhusi M , Bennett V , Grant AO . 2000. Abnormal cardiac Na channel properties and QT heart rate adaptation in neonatal ankyrin knockout mice. Circ Res 86:441-447. Google Scholar, Crossref, Medline, ISI | |
| Chen C , Cannon SC . 1995. Modulation of Na channel inactivation by the β1 subunit: a deletion analysis. Eur J Physiol 431:186-195. Google Scholar, Crossref, Medline, ISI | |
| Davis JQ , Lambert S , Bennett V . 1996. Molecular composition of the node of Ranvier: identification of ankyrin-binding cell adhesion molecules neurofascin (mucin +/third FNIII domain-) and NrCAM at nodal axon segments. J Cell Biol 135:1355-1367. Google Scholar, Crossref, Medline, ISI | |
| Dib-Hajj SD , Hinson AW , Black JA , Waxman SG . 1996. Sodium channel mRNA in the B104 neuroblastoma cell line. FEBS Lett 384:78-82. Google Scholar, Crossref, Medline, ISI | |
| Escayg A , MacDonald BT , Meisler MH , Baulac S , Huberfeld G , An-Gourfinkel I , and others . 2000. Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nat Genet 24:343-345. Google Scholar, Crossref, Medline, ISI | |
| Faissner A . 1997. The tenascin gene family in axon growth and guidance. Cell Tissue Res 290:331-341. Google Scholar, Crossref, Medline, ISI | |
| Garver TD , Ren Q , Tuvia S , Bennett V . 1997. Tyrosine phosphorylation at a site highly conserved in the L1 family of cell adhesion molecules abolishes ankyrin binding and increases lateral mobility of neurofascin. J Cell Biol 137:703-714. Google Scholar, Crossref, Medline, ISI | |
| Gee SH , Madhavan R , Levinson SR , Caldwell JH , Sealock R , Froehner SC . 1998. Interaction of muscle and brain sodium channels with multiple members of the syntrophin family of dystrophin-associated proteins. J Neurosci 18:128-137. Google Scholar, Medline, ISI | |
| Goldin AL . 1993. Accessory subunits and sodium channel inactivation. Curr Opin Neurobiol 3:272-277. Google Scholar, Crossref, Medline | |
| Gurnett CA , Campbell KP . 1996. Transmembrane auxiliary subunits of voltage-dependent ion channels. J Biol Chem 271:27975-27978. Google Scholar, Crossref, Medline, ISI | |
| Hortsch M , Bieber AJ . 1991. Sticky molecules in not-so-sticky cells. Trends Biol Sci 16:283-287. Google Scholar, Crossref, Medline, ISI | |
| Isom LL , Catterall WA . 1996. Na channel subunits and Ig domains. Nature 383:307-308. Google Scholar, Crossref, Medline, ISI | |
| Isom LL , De Jongh KS , Catterall WA . 1994. Auxiliary subunits of voltage-gated ion channels. Neuron 12:1183-1194. Google Scholar, Crossref, Medline, ISI | |
| Isom LL , De Jongh KS , Patton DE , Reber BFX , Offord J , Charbonneau H , and others . 1992. Primary structure and functional expression of the β1 subunit of the rat brain sodium channel. Science 256:839-842. Google Scholar, Crossref, Medline, ISI | |
| Isom LL , Ragsdale DS , De Jongh KS , Westenbroek RE , Reber BF , Scheuer T , and others . 1995. Structure and function of the β2 subunit of brain sodium channels, a transmembrane glycoprotein with a CAM motif. Cell 83:433-442. Google Scholar, Crossref, Medline, ISI | |
| Isom LL , Scheuer T , Brownstein AB , Ragsdale DS , Murphy BJ , Catterall WA . 1994. Functional co-expression of the β1 and type IIA α subunits of sodium channels in a mammalian cell line. J Biol Chem 270:3306-3312. Google Scholar, Crossref, ISI | |
| Kamiguchi H , Lemmon V . 1997. Neural cell adhesion molecule L1: signalling pathways and growth cone motility. J Neurosci Methods 49:1-8. Google Scholar | |
| Kazen-Gillespie KA , Ragsdale DS , D’Andrea MR , Mattei LN , Rogers KE , Isom LL . 2000. Cloning, localization, and functional expression of sodium channel β1A subunits. J Biol Chem 275:1079-1088. Google Scholar, Crossref, Medline, ISI | |
| Kordeli E , Davis J , Trapp B , Bennett V . 1990. An isoform of ankyrin is localized at nodes of Ranvier in myelinated axons of central and peripheral nerves. J Cell Biol 110:1341-1352. Google Scholar, Crossref, Medline, ISI | |
| Ma JY , Catterall WA , Scheuer T . 1997. Persistent sodium currents through brain sodium channels induced by G protein βγ subunits. Neuron 19:443-452. Google Scholar, Crossref, Medline, ISI | |
| Ma JY , Li M , Catterall WA , Scheuer T . 1994. Modulation of brain Na channels by a G-protein-coupled pathway. Proc Natl Acad Sci U S A 91:12351-12355. Google Scholar, Crossref, Medline, ISI | |
| Makita N , Bennett PB , George AL . 1996. Molecular determinants of β1 subunit-induced gating modulation in voltage-dependant Na channels. J Neurosci 16:7117-7127. Google Scholar, Medline, ISI | |
| Malhotra JD , Kazen-Gillespie K , Hortsch M , Isom LL . 2000. Sodium channel β subunits mediate homophilic cell adhesion and recruit ankyrin to points of cell-cell contact. J Biol Chem 275:11383-11388. Google Scholar, Crossref, Medline, ISI | |
| Malhotra JD , Meadows L , Ragsdale DS , Hortsch M , Isom LL . 1999. Cytoplasmic domains of voltage-gated sodium channel β subunits are essential for ankyrin recruitment and channel modulation in heterologous expression systems. Soc Neurosci Abstr 25:1731. Google Scholar | |
| McCormick KA , Isom LL , Ragsdale D , Smith D , Scheuer T , Catterall WA . 1998. Molecular determinants of Na channel function in the extracellular domain of the beta1 subunit. J Biol Chem 273:3954-3962. Google Scholar, Crossref, Medline, ISI | |
| McCormick KA , Srinivasan J , White K , Scheuer T , Catterall WA . 1999. The extracellular domain of the β1 subunit is both necessary and sufficient for β1-like modulation of sodium channel gating. J Biol Chem 274:32638-32646. Google Scholar, Crossref, Medline, ISI | |
| Meadows L , Malhotra JD , Stetzer A , Isom LL , Ragsdale DS . In press. The intracellular segment of the sodium channel β1 subunit is required for functional modulation of brain sodium channel expressed in a mammalian cell line. J Neurochem. Google Scholar | |
| Michaely P , Bennett V . 1993. The membrane-binding domain of ankyrin contains four independently folded subdomains, each comprised of six ankyrin repeats. J Biol Chem 268:22703-22709. Google Scholar, Medline, ISI | |
| Morgan K , Stevens EB , Shah B , Cox PJ , Dixon AK , Lee K , and others . 2000. β3: an additional auxiliary subunit of the voltage-sensitive sodium channel that modulates channel gating with distinct kinetics. Proc Natl Acad Sci U S A 97:2308-2313. Google Scholar, Crossref, Medline, ISI | |
| Muller-Husmann G , Gloor S , Schachner M . 1993. Functional characterization of beta isoforms of murine Na, K-ATPase. The adhesion molecule on glia (AMOG/beta 2), but not beta 1, promotes neurite outgrowth. J Biol Chem 268:26260-26267. Google Scholar, Medline, ISI | |
| Oh Y , Lee YJ , Waxman SG . 1997. Regulation of Na channel β1 and β2 subunit mRNA levels in cultured rat astrocytes. Neurosci Lett 234:107-110. Google Scholar, Crossref, Medline, ISI | |
| Oh Y , Waxman SG . 1994. The β1 subunit mRNA of the rat brain Na channel is expressed in glial cells. Proc Natl Acad Sci U S A 91:9985-9989. Google Scholar, Crossref, Medline, ISI | |
| Peles E , Nativ M , Campbell PL , Sakurai T , Martinez R , Lev S , and others . 1995. The carbonic anhydrase domain of receptor tyrosine phosphatase beta is a functional ligand for the axonal cell recognition molecule contactin. Cell 82:251-260. Google Scholar, Crossref, Medline, ISI | |
| Plummer NW , Meisler MH . 1999. Evolution and diversity of mammalian sodium channel genes. Genomics 57:323-331. Google Scholar, Crossref, Medline, ISI | |
| 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. Google Scholar, Crossref, Medline, ISI | |
| Ratcliffe CF , Qu Y , McCormick KA , Tibbs VC , Dixon JE , Scheuer T , and others . 2000. A sodium channel signaling complex: modulation by associated receptor protein tyrosine phosphatase β. Nat Neurosci 3:437-444. Google Scholar, Crossref, Medline, ISI | |
| Sampo B , Tricaud N , Leveque C , Seagar M , Couraud F , Dargent B . 2000. Direct interaction between synaptotagmin and the intracellular loop I-II of neuronal voltage-sensitive sodium channels. Proc Natl Acad Sci U S A 97:3666-3671. Google Scholar, Crossref, Medline, ISI | |
| Sangameswaran L , Delgado SG , Fish LM , Koch BD , Jakeman LB , Stewart R , and others . 1996. Structure and function of a novel voltage-gated, tetrodotoxin-resistant sodium channel specific to sensory neurons. J Biol Chem 271:5953-5956. Google Scholar, Crossref, Medline, ISI | |
| Schachner M . 1997. Neural recognition molecules and synaptic plasticity. Curr Opin Cell Biol 9:627-634. Google Scholar, Crossref, Medline, ISI | |
| Schmidt J , Rossie S , Catterall WA . 1985. A large intracellular pool of inactive Na channel alpha subunits in developing rat brain. Proc Natl Acad Sci U S A 82:4847-4851. Google Scholar, Crossref, Medline, ISI | |
| Schmidt JW , Catterall WA . 1986. Biosynthesis and processing of the alpha subunit of the voltage-sensitive sodium channel in rat brain neurons. Cell 46:437-445. Google Scholar, Crossref, Medline, ISI | |
| Sharp AA , Caldwell JH . 1996. Aggregation of sodium channels induced by a postnatally upregulated isoform of agrin. J Neurosci 16:6775-6783. Google Scholar, Medline, ISI | |
| Shcherbatko A , Ono F , Mandel G , Brehm P . 1999. Voltage-dependent sodium channel function is regulated through membrane mechanics. Biophys J 77:1945-1959. Google Scholar, Crossref, Medline, ISI | |
| Souslova VA , Fox M , Wood JN , Akopian AN . 1997. Cloning and characterization of a mouse sensory neuron tetrodotoxin-resistant voltage-gated sodium channel gene, Scn10a. Genomics 41:201-209. Google Scholar, Crossref, Medline, ISI | |
| Srinivasan J , Schachner M , Catterall WA . 1998. Interaction of voltage-gated sodium channels with the extracellular matrix molecules tenascin-C and tenascin-R. Proc Natl Acad Sci U S A 95:15753-15757. Google Scholar, Crossref, Medline, ISI | |
| Undrovinas AI , Shander GS , Makielski JC . 1995. Cytoskeleton modulates gating of voltage-dependent sodium channel in heart. Am J Physiol 269:H203-H214. Google Scholar, Medline, ISI | |
| Wallace RH , Wang DW , Singh R , Scheffer IE , George AL Jr , Phillips HA , and others . 1998. Febrile seizures and generalized epilepsy associated with a mutation in the Na -channel beta1 subunit gene SCN1B. Nat Genet 19:366-370. Google Scholar, Crossref, Medline, ISI | |
| Weber P , Bartsch U , Rasband MN , Czaniera R , Lang Y , Bluethmann H , and others . 1999. Mice deficient for tenascin-R display alterations of the extracellular matrix and decreased axonal conduction velocities in the CNS. J Neurosci 19:4245-4262. Google Scholar, Medline, ISI | |
| Wood SJ , Slater CR . 1998. β-spectrin is colocalized with both voltage-gated sodium channels and ankyrin at the adult rat neuromuscular junction. J Cell Biol 140:675-684. Google Scholar, Crossref, Medline, ISI | |
| Xiao Z-C , Ragsdale DS , Malhorta JD , Mattei LN , Brauns PE , Schachner M , and others . 1999. Tenascin-R is a functional modulator of sodium channel β subunits. J Biol Chem 274:26511-26517. Google Scholar, Crossref, Medline, ISI |
