Summary
Voltage-gated sodium (Nav) channels are critical players in the generation and propagation of action potentials by triggering membrane depolarization. Mutations in Nav channels are associated with a variety of channelopathies, which makes them relevant targets for pharmaceutical intervention. So far, the cryoelectron microscopic structure of the human Nav1.2, Nav1.4, and Nav1.7 has been reported, which sheds light on the molecular basis of functional mechanism of Nav channels and provides a path toward structure-based drug discovery. In this review, we focus on the recent advances in the structure, molecular mechanism and modulation of Nav channels, and state updated sodium channel blockers for the treatment of pathophysiology disorders and briefly discuss where the blockers may be developed in the future.
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11 January 2021
An Erratum to this paper has been published: https://doi.org/10.1007/s11596-020-2279-9
References
Ahern CA, Payandeh J, Bosmans F, et al. The hitchhiker’s guide to the voltage-gated sodium channel galaxy. J Gen Physiol, 2016,147(1):1–24
Carnevale V, Klein ML. Small molecule modulation of voltage gated sodium channels. Curr Opin Struct Biol, 2017,43:156–162
Huang W, Liu M, Yan SF, et al. Structure-based assessment of disease-related mutations in human voltage-gated sodium channels. Protein Cell, 2017,8(6):401–438
Catterall WA. Forty Years of Sodium Channels: Structure, Function, Pharmacology, and Epilepsy. Neurochem Res, 2017,42(9):2495–2504
Catterall WA. Sodium channels, inherited epilepsy, and antiepileptic drugs. Annu Rev Pharmacol Toxicol, 2014,54:317–338
Rubinstein M, Patowary A, Stanaway IB, et al. Association of rare missense variants in the second intracellular loop of NaV1.7 sodium channels with familial autism. Mol Psychiatry, 2018,23(2):231–239
Luiz AP, Wood JN. Sodium Channels in Pain and Cancer: New Therapeutic Opportunities. Adv Pharmacol, 2016,75:153–178
Dib-Hajj SD, Yang Y, Black JA, et al. The Na(V)1.7 sodium channel: from molecule to man. Nat Rev Neurosci, 2013,14(1):49–62
Dib-Hajj SD, Cummins TR, Black JA, et al. Sodium channels in normal and pathological pain. Annu Rev Neurosci, 2010,33:325–347
Pedraza Escalona M, Possani LD. Scorpion beta-toxins and voltage-gated sodium channels: interactions and effects. Front Biosci (Landmark Ed), 2013,18:572–587
Bagal SK, Marron BE, Owen RM, et al. Voltage gated sodium channels as drug discovery targets. Channels (Austin), 2015,9(6):360–366
Payandeh J, Scheuer T, Zheng N, et al. The crystal structure of a voltage-gated sodium channel. Nature, 2011,475(7356):353–358
Payandeh J, Gamal El-Din TM, Scheuer T, et al. Crystal structure of a voltage-gated sodium channel in two potentially inactivated states. Nature, 2012,486(7401):135–139
Zhang X, Ren W, DeCaen P, et al. Crystal structure of an orthologue of the NaChBac voltage-gated sodium channel. Nature, 2012,486(7401):130–134
McCusker EC, Bagneris C, Naylor CE, et al. Structure of a bacterial voltage-gated sodium channel pore reveals mechanisms of opening and closing. Nat Commun, 2012,3:1102–1109
Shen H, Zhou Q, Pan X, et al. Structure of a eukaryotic voltage-gated sodium channel at near-atomic resolution. Science, 2017,355(6328):eaal4326
Yan Z, Zhou Q, Wang L, et al. Structure of the Nav1.4-beta1 Complex from Electric Eel. Cell, 2017,170(3):470–482 e11
Shen H, Li Z, Jiang Y, et al. Structural basis for the modulation of voltage-gated sodium channels by animal toxins. Science, 2018,362(6412):eaau2596
Pan X, Li Z, Zhou Q, et al. Structure of the human voltage-gated sodium channel Nav1.4 in complex with beta1. Science, 2018,362(6412):eaau2486
Shen H, Liu D, Wu K, et al. Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins. Science, 2019,363(6433):1303–1308
Pan X, Li Z, Huang X, et al. Molecular basis for pore blockade of human Na(+) channel Nav1.2 by the muconotoxin KIIIA. Science, 2019,363(6433):1309–1313
Catterall WA. Voltage-gated sodium channels at 60: structure, function and pathophysiology. J Physiol, 2012,590(11):2577–2589
Corry B, Thomas M. Mechanism of ion permeation and selectivity in a voltage gated sodium channel. J Am Chem Soc, 2012,134(3):1840–1846
de Lera Ruiz, M, Kraus RL. Voltage-Gated Sodium Channels: Structure, Function, Pharmacology, and Clinical Indications. J Med Chem, 2015,58(18):7093–7118
Bagal SK, Brown AD, Cox PJ, et al. Ion channels as therapeutic targets: a drug discovery perspective. J Med Chem, 2013,56(3):593–624
Stock L, Souza C, Treptow W. Structural basis for activation of voltage-gated cation channels. Biochemistry, 2013,52(9):1501–1513
Stock L, Delemotte L, Carnevale V, et al. Conduction in a biological sodium selective channel. J Phys Chem B, 2013,117(14):3782–3789
Favre I, Moczydlowski E, Schild L. On the structural basis for ionic selectivity among Na+, K+, and Ca2+ in the voltage-gated sodium channel. Biophys J, 1996,71(6):3110–3125
Shaya D, Findeisen F, Abderemane-Ali F, et al. Structure of a prokaryotic sodium channel pore reveals essential gating elements and an outer ion binding site common to eukaryotic channels. J Mol Biol, 2014,426(2):467–483
Palovcak E, Delemotte L, Klein ML, et al. Evolutionary imprint of activation: the design principles of VSDs. J Gen Physiol, 2014,143(2):145–156
Patton DE, West JW, Catterall WA, et al. Amino acid residues required for fast Na(+)-channel inactivation: charge neutralizations and deletions in the III-IV linker. Proc Natl Acad Sci USA, 1992,89(22):10905–10909
Kalia J, Milescu M, Salvatierra J, et al. From foe to friend: using animal toxins to investigate ion channel function. J Mol Biol, 2015,427(1):158–175
Laedermann CJ, Syam N, Pertin M, et al. beta1- and beta3- voltage-gated sodium channel subunits modulate cell surface expression and glycosylation of Nav1.7 in HEK293 cells. Front Cell Neurosci, 2013,7:137–158
Xu H, Li T, Rohou A, et al. Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin. Cell, 2019,176(4):702–715
Hoeijmakers JG, Faber CG, Merkies IS, et al. Painful peripheral neuropathy and sodium channel mutations. Neurosci Lett, 2015,596:51–59
Habib AM, Wood JN, Cox JJ. Sodium channels and pain. Handb Exp Pharmacol, 2015,227:39–56
Dib-Hajj SD, Black JA, Waxman SG. NaV1.9: a sodium channel linked to human pain. Nat Rev Neurosci, 2015,16(9):511–519
Sun S, Jia Q, Zenova AY, et al. Identification of Selective Acyl Sulfonamide-Cycloalkylether Inhibitors of the Voltage-Gated Sodium Channel (NaV) 1.7 with Potent Analgesic Activity. J Med Chem, 2019,62(2):908–927
Lee JH, Park CK, Chen G, et al. A monoclonal antibody that targets a NaV1.7 channel voltage sensor for pain and itch relief. Cell, 2014,157(6):1393–1404
Black JA, Nikolajsen L, Kroner K, et al. Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann Neurol, 2008,64(6):644–653
Hameed S. Nav1.7 and Nav1.8: Role in the pathophysiology of pain. Mol Pain, 2019,15:1–11
Cregg R, Laguda B, Werdehausen R, et al. Novel mutations mapping to the fourth sodium channel domain of Nav1.7 result in variable clinical manifestations of primary erythromelalgia. Neuromolecular Med, 2013,15(2):265–278
Faber CG, Hoeijmakers JG, Ahn HS, et al. Gain of function Nanu1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol, 2012,71(1):26–39
Faber CG, Lauria G, Merkies IS, et al. Gain-of-function Nav1.8 mutations in painful neuropathy. Proc Natl Acad Sci USA, 2012,109(47):19444–19449
Zhang XY, Wen J, Yang W, et al. Gain-of-function mutations in SCN11A cause familial episodic pain. Am J Hum Genet, 2013,93(5):957–966
Shao N, Zhang H, Wang X, et al. Familial Hemiplegic Migraine Type 3 (FHM3) with an SCN1A Mutation in a Chinese Family: A Case Report. Front Neurol, 2018,9:976–984
Cestele S, Labate A, Rusconi R, et al. Divergent effects of the T1174S SCN1A mutation associated with seizures and hemiplegic migraine. Epilepsia, 2013,54(5):927–935
Mantegazza M, Curia G, Biagini G, et al. Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders. Lancet Neurol, 2010,9(4):413–424
Fujiwara T, Sugawara T, Mazaki-Miyazaki E, et al. Mutations of sodium channel alpha subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic-clonic seizures. Brain, 2003,126(Pt 3):531–546
Catterall WA, Kalume F, Oakley JC. NaV1.1 channels and epilepsy. J Physiol, 2010,588(Pt 11):1849–1859
Tao YX. Pharmacology and therapeutics of constitutively active receptors. Preface. Adv Pharmacol, 2014,70:ix–x
Han D, Tan H, Sun C, et al. Dysfunctional Nav1.5 channels due to SCN5A mutations. Exp Biol Med (Maywood), 2018,243(10):852–863
Antzelevitch C, Nesterenko V, Shryock JC, et al. The role of late I Na in development of cardiac arrhythmias. Handb Exp Pharmacol, 2014,221:137–168
van den Boogaard M, Smemo S, Burnicka-Turek O, et al. A common genetic variant within SCN10A modulates cardiac SCN5A expression. J Clin Invest, 2014,124(4):1844–1852
Vucic S, Kiernan MC. Upregulation of persistent sodium conductances in familial ALS. J Neurol Neurosurg Psychiatry, 2010,81(2):222–227
Wang Y, Zhang J, Liu B, et al. Genetic polymorphisms in the SCN8A gene are associated with suicidal behavior in psychiatric disorders in the Chinese population. World J Biol Psychiatry, 2010,11(8):956–963
Riva D, Vago C, Pantaleoni C, et al. Progressive neurocognitive decline in two children with Dravet syndrome, de novo SCN1A truncations and different epileptic phenotypes. Am J Med Genet A, 2009,149A(10):2339–2345
Mao W, Zhang J, Korner H, et al. The Emerging Role of Voltage-Gated Sodium Channels in Tumor Biology. Front Oncol, 2019,9:124–143
Busco G, Cardone RA, Greco MR, et al. NHE1 promotes invadopodial ECM proteolysis through acidification of the peri-invadopodial space. FASEB J, 2010,24(10):3903–3915
Brisson L, Gillet L, Calaghan S, et al. Na(V)1.5 enhances breast cancer cell invasiveness by increasing NHE1-dependent H(+) efflux in caveolae. Oncogene, 2011,30(17):2070–2076
Yang M, Kozminski DJ, Wold LA, et al. Therapeutic potential for phenytoin: targeting Na(v)1.5 sodium channels to reduce migration and invasion in metastatic breast cancer. Breast Cancer Res Treat, 2012,134(2):603–615
McCormack K, Santos S, Chapman ML, et al. Voltage sensor interaction site for selective small molecule inhibitors of voltage-gated sodium channels. Proc Natl Acad Sci U S A, 2013,110(29):E2724–E2732
Deuis JR, Wingerd JS, Winter Z, et al. Analgesic Effects of GpTx-1, PF-04856264 and CNV1014802 in a Mouse Model of NaV1.7-Mediated Pain. Toxins (Basel), 2016,8(3):78–104
Ahuja S, Mukund S, Deng L, et al. Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist. Science, 2015,350(6267):aac5464
Goldberg YP, Price N, Namdari R, et al. Treatment of Na(v)1.7-mediated pain in inherited erythromelalgia using a novel sodium channel blocker. Pain, 2012,153(1):80–85
Bagal SK, Chapman ML, Marron BE, et al. Recent progress in sodium channel modulators for pain. Bioorg Med Chem Lett, 2014,24(16):3690–3699
Emery EC, Luiz AP, Wood JN. Nav1.7 and other voltage-gated sodium channels as drug targets for pain relief. Expert Opin Ther Targets, 2016,20(8):975–983
Bagal SK, Bungay PJ, Denton SM, et al. Discovery and Optimization of Selective Nav1.8 Modulator Series That Demonstrate Efficacy in Preclinical Models of Pain. ACS Med Chem Lett, 2015,6(6):650–654
Graceffa RF, Boezio AA, Able J, et al. Sulfonamides as Selective NaV1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity. J Med Chem, 2017,60(14):5990–6017
Bankar G, Goodchild SJ, Howard S, et al. Selective NaV1.7 Antagonists with Long Residence Time Show Improved Efficacy against Inflammatory and Neuropathic Pain. Cell Rep, 2018,24(12):3133–3145
Catterall WA. Ion channel voltage sensors: structure, function, and pathophysiology. Neuron, 2010,67(6):915–928
Cestele S, Qu Y, Rogers JC, et al. Voltage sensor-trapping: enhanced activation of sodium channels by beta-scorpion toxin bound to the S3–S4 loop in domain II. Neuron, 1998,21(4):919–931
Heinemann SH, Leipold E. Conotoxins of the O-superfamily affecting voltage-gated sodium channels. Cell Mol Life Sci, 2007,64(11):1329–1340
Xiao Y, Blumenthal K, Jackson JO, 2nd, et al. The tarantula toxins ProTx-II and huwentoxin-IV differentially interact with human Nav1.7 voltage sensors to inhibit channel activation and inactivation. Mol Pharmacol, 2010,78(6):1124–1134
Chiossi L, Negro A, Capi M, et al. Sodium channel antagonists for the treatment of migraine. Expert Opin Pharmacother, 2014,15(12):1697–1706
Errington AC, Stohr T, Heers C, et al. The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels. Mol Pharmacol, 2008,73(1):157–169
Shaheen U, Akka J, Hinore JS, et al. Computer aided identification of sodium channel blockers in the clinical treatment of epilepsy using molecular docking tools. Bioinformation, 2015,11(3):131–137
Caccamo D, Pisani LR, Mazzocchetti P, et al. Neuroprotection as a Potential Therapeutic Perspective in Neurodegenerative Diseases: Focus on Antiepileptic Drugs. Neurochem Res, 2016,41(1–2):340–352
Jensen HS, Grunnet M, Bastlund JF. Therapeutic potential of Na(V)1.1 activators. Trends Pharmacol Sci, 2014,35(3):113–118
Black JA, Waxman SG. Noncanonical roles of voltage-gated sodium channels. Neuron, 2013,80(2):280–291
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Conflict of Interest Statement
The authors claim that the researchers in this study have no conflict of interest.
The original version of this article was revised due to a retrospective Open Access order.
This work was supported by the National Natural Science Foundation of China (Nos. 81473254, 81773637, 81773594, U1703111), and the Fundamental Research Fund for the Central Universities (No. 2017KFYXJJ151).
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Li, Zm., Chen, Lx. & Li, H. Voltage-gated Sodium Channels and Blockers: An Overview and Where Will They Go?. CURR MED SCI 39, 863–873 (2019). https://doi.org/10.1007/s11596-019-2117-0
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DOI: https://doi.org/10.1007/s11596-019-2117-0