Voltage-gated Sodium Channels and Blockers: An Overview and Where Will They Go?

Abstract

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.

Keywords

voltage-gated sodium channels / blockers / Nav channel structures / channelopathies

References

[1] AhernCA, PayandehJ, BosmansF, et al.. The hitchhiker’s guide to the voltage-gated sodium channel galaxy. J Gen Physiol, 2016, 147(1): 1-24

[2] CarnevaleV, KleinML. Small molecule modulation of voltage gated sodium channels. Curr Opin Struct Biol, 2017, 43: 156-162

[3] HuangW, LiuM, YanSF, et al.. Structure-based assessment of disease-related mutations in human voltage-gated sodium channels. Protein Cell, 2017, 8(6): 401-438

[4] CatterallWA. Forty Years of Sodium Channels: Structure, Function, Pharmacology, and Epilepsy. Neurochem Res, 2017, 42(9): 2495-2504

[5] CatterallWA. Sodium channels, inherited epilepsy, and antiepileptic drugs. Annu Rev Pharmacol Toxicol, 2014, 54: 317-338

[6] RubinsteinM, PatowaryA, StanawayIB, 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

[7] LuizAP, WoodJN. Sodium Channels in Pain and Cancer: New Therapeutic Opportunities. Adv Pharmacol, 2016, 75: 153-178

[8] Dib-HajjSD, YangY, BlackJA, et al.. The Na(V)1.7 sodium channel: from molecule to man. Nat Rev Neurosci, 2013, 14(1): 49-62

[9] Dib-HajjSD, CumminsTR, BlackJA, et al.. Sodium channels in normal and pathological pain. Annu Rev Neurosci, 2010, 33: 325-347

[10] Pedraza EscalonaM, PossaniLD. Scorpion beta-toxins and voltage-gated sodium channels: interactions and effects. Front Biosci (Landmark Ed), 2013, 18: 572-587

[11] BagalSK, MarronBE, OwenRM, et al.. Voltage gated sodium channels as drug discovery targets. Channels (Austin), 2015, 9(6): 360-366

[12] PayandehJ, ScheuerT, ZhengN, et al.. The crystal structure of a voltage-gated sodium channel. Nature, 2011, 475(7356): 353-358

[13] PayandehJ, Gamal El-DinTM, ScheuerT, et al.. Crystal structure of a voltage-gated sodium channel in two potentially inactivated states. Nature, 2012, 486(7401): 135-139

[14] ZhangX, RenW, DeCaenP, et al.. Crystal structure of an orthologue of the NaChBac voltage-gated sodium channel. Nature, 2012, 486(7401): 130-134

[15] McCuskerEC, BagnerisC, NaylorCE, et al.. Structure of a bacterial voltage-gated sodium channel pore reveals mechanisms of opening and closing. Nat Commun, 2012, 3: 1102-1109

[16] ShenH, ZhouQ, PanX, et al.. Structure of a eukaryotic voltage-gated sodium channel at near-atomic resolution. Science, 2017, 355(6328): eaal4326

[17] YanZ, ZhouQ, WangL, et al.. Structure of the Nav1.4-beta1 Complex from Electric Eel. Cell, 2017, 170(3): 470-482 e11

[18] ShenH, LiZ, JiangY, et al.. Structural basis for the modulation of voltage-gated sodium channels by animal toxins. Science, 2018, 362(6412): eaau2596

[19] PanX, LiZ, ZhouQ, et al.. Structure of the human voltage-gated sodium channel Nav1.4 in complex with beta1. Science, 2018, 362(6412): eaau2486

[20] ShenH, LiuD, WuK, et al.. Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins. Science, 2019, 363(6433): 1303-1308

[21] PanX, LiZ, HuangX, et al.. Molecular basis for pore blockade of human Na(+) channel Nav1.2 by the muconotoxin KIIIA. Science, 2019, 363(6433): 1309-1313

[22] CatterallWA. Voltage-gated sodium channels at 60: structure, function and pathophysiology. J Physiol, 2012, 590(11): 2577-2589

[23] CorryB, ThomasM. Mechanism of ion permeation and selectivity in a voltage gated sodium channel. J Am Chem Soc, 2012, 134(3): 1840-1846

[24] de Lera RuizM, KrausRL. Voltage-Gated Sodium Channels: Structure, Function, Pharmacology, and Clinical Indications. J Med Chem, 2015, 58(18): 7093-7118

[25] BagalSK, BrownAD, CoxPJ, et al.. Ion channels as therapeutic targets: a drug discovery perspective. J Med Chem, 2013, 56(3): 593-624

[26] StockL, SouzaC, TreptowW. Structural basis for activation of voltage-gated cation channels. Biochemistry, 2013, 52(9): 1501-1513

[27] StockL, DelemotteL, CarnevaleV, et al.. Conduction in a biological sodium selective channel. J Phys Chem B, 2013, 117(14): 3782-3789

[28] FavreI, MoczydlowskiE, SchildL. 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

[29] ShayaD, FindeisenF, Abderemane-AliF, 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

[30] PalovcakE, DelemotteL, KleinML, et al.. Evolutionary imprint of activation: the design principles of VSDs. J Gen Physiol, 2014, 143(2): 145-156

[31] PattonDE, WestJW, CatterallWA, 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

[32] KaliaJ, MilescuM, SalvatierraJ, et al.. From foe to friend: using animal toxins to investigate ion channel function. J Mol Biol, 2015, 427(1): 158-175

[33] LaedermannCJ, SyamN, PertinM, 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

[34] XuH, LiT, RohouA, et al.. Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin. Cell, 2019, 176(4): 702-715

[35] HoeijmakersJG, FaberCG, MerkiesIS, et al.. Painful peripheral neuropathy and sodium channel mutations. Neurosci Lett, 2015, 596: 51-59

[36] HabibAM, WoodJN, CoxJJ. Sodium channels and pain. Handb Exp Pharmacol, 2015, 227: 39-56

[37] Dib-HajjSD, BlackJA, WaxmanSG. NaV1.9: a sodium channel linked to human pain. Nat Rev Neurosci, 2015, 16(9): 511-519

[38] SunS, JiaQ, ZenovaAY, 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

[39] LeeJH, ParkCK, ChenG, et al.. A monoclonal antibody that targets a NaV1.7 channel voltage sensor for pain and itch relief. Cell, 2014, 157(6): 1393-1404

[40] BlackJA, NikolajsenL, KronerK, et al.. Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann Neurol, 2008, 64(6): 644-653

[41] HameedS. Nav1.7 and Nav1.8: Role in the pathophysiology of pain. Mol Pain, 2019, 15: 1-11

[42] CreggR, LagudaB, WerdehausenR, 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

[43] FaberCG, HoeijmakersJG, AhnHS, et al.. Gain of function Nanu1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol, 2012, 71(1): 26-39

[44] FaberCG, LauriaG, MerkiesIS, et al.. Gain-of-function Nav1.8 mutations in painful neuropathy. Proc Natl Acad Sci USA, 2012, 109(47): 19444-19449

[45] ZhangXY, WenJ, YangW, et al.. Gain-of-function mutations in SCN11A cause familial episodic pain. Am J Hum Genet, 2013, 93(5): 957-966

[46] ShaoN, ZhangH, WangX, 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

[47] CesteleS, LabateA, RusconiR, et al.. Divergent effects of the T1174S SCN1A mutation associated with seizures and hemiplegic migraine. Epilepsia, 2013, 54(5): 927-935

[48] MantegazzaM, CuriaG, BiaginiG, et al.. Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders. Lancet Neurol, 2010, 9(4): 413-424

[49] FujiwaraT, SugawaraT, Mazaki-MiyazakiE, et al.. Mutations of sodium channel alpha subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic-clonic seizures. Brain, 2003, 126(Pt3): 531-546

[50] CatterallWA, KalumeF, OakleyJC. NaV1.1 channels and epilepsy. J Physiol, 2010, 588(Pt11): 1849-1859

[51] TaoYX. Pharmacology and therapeutics of constitutively active receptors. Preface. Adv Pharmacol, 2014, 70: ix-x

[52] HanD, TanH, SunC, et al.. Dysfunctional Nav1.5 channels due to SCN5A mutations. Exp Biol Med (Maywood), 2018, 243(10): 852-863

[53] AntzelevitchC, NesterenkoV, ShryockJC, et al.. The role of late I Na in development of cardiac arrhythmias. Handb Exp Pharmacol, 2014, 221: 137-168

[54] van den BoogaardM, SmemoS, Burnicka-TurekO, et al.. A common genetic variant within SCN10A modulates cardiac SCN5A expression. J Clin Invest, 2014, 124(4): 1844-1852

[55] VucicS, KiernanMC. Upregulation of persistent sodium conductances in familial ALS. J Neurol Neurosurg Psychiatry, 2010, 81(2): 222-227

[56] WangY, ZhangJ, LiuB, 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

[57] RivaD, VagoC, PantaleoniC, 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

[58] MaoW, ZhangJ, KornerH, et al.. The Emerging Role of Voltage-Gated Sodium Channels in Tumor Biology. Front Oncol, 2019, 9: 124-143

[59] BuscoG, CardoneRA, GrecoMR, et al.. NHE1 promotes invadopodial ECM proteolysis through acidification of the peri-invadopodial space. FASEB J, 2010, 24(10): 3903-3915

[60] BrissonL, GilletL, CalaghanS, 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

[61] YangM, KozminskiDJ, WoldLA, 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

[62] McCormackK, SantosS, ChapmanML, 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

[63] DeuisJR, WingerdJS, WinterZ, 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

[64] AhujaS, MukundS, DengL, et al.. Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist. Science, 2015, 350(6267): aac5464

[65] GoldbergYP, PriceN, NamdariR, 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

[66] BagalSK, ChapmanML, MarronBE, et al.. Recent progress in sodium channel modulators for pain. Bioorg Med Chem Lett, 2014, 24(16): 3690-3699

[67] EmeryEC, LuizAP, WoodJN. Nav1.7 and other voltage-gated sodium channels as drug targets for pain relief. Expert Opin Ther Targets, 2016, 20(8): 975-983

[68] BagalSK, BungayPJ, DentonSM, 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

[69] GraceffaRF, BoezioAA, AbleJ, 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

[70] BankarG, GoodchildSJ, HowardS, 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

[71] CatterallWA. Ion channel voltage sensors: structure, function, and pathophysiology. Neuron, 2010, 67(6): 915-928

[72] CesteleS, QuY, RogersJC, 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

[73] HeinemannSH, LeipoldE. Conotoxins of the O-superfamily affecting voltage-gated sodium channels. Cell Mol Life Sci, 2007, 64(11): 1329-1340

[74] XiaoY, BlumenthalK, JacksonJO2nd, 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

[75] ChiossiL, NegroA, CapiM, et al.. Sodium channel antagonists for the treatment of migraine. Expert Opin Pharmacother, 2014, 15(12): 1697-1706

[76] ErringtonAC, StohrT, HeersC, et al.. The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels. Mol Pharmacol, 2008, 73(1): 157-169

[77] ShaheenU, AkkaJ, HinoreJS, 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

[78] CaccamoD, PisaniLR, MazzocchettiP, et al.. Neuroprotection as a Potential Therapeutic Perspective in Neurodegenerative Diseases: Focus on Antiepileptic Drugs. Neurochem Res, 2016, 41(1–2): 340-352

[79] JensenHS, GrunnetM, BastlundJF. Therapeutic potential of Na(V)1.1 activators. Trends Pharmacol Sci, 2014, 35(3): 113-118

[80] BlackJA, WaxmanSG. Noncanonical roles of voltage-gated sodium channels. Neuron, 2013, 80(2): 280-291