Publish with Nova Science Publishers
We publish over 800 titles annually by leading researchers from around the world. Submit a Book Proposal Now!
$39.50
Akihiko Sunami¹ and Tatsuo Munakata²
¹School of Pharmacy, Department of Pharmaceutical Sciences, International University of Health and Welfare, Otawara, Tochigi, Japan
²School of Pharmacy at Fukuoka, Department of Pharmaceutical Sciences, International University of Health and Welfare, Okawa, Fukuoka, Japan
Part of the book: Advances in Health and Disease. Volume 63
Voltage-gated sodium channels (Navs) are membrane proteins responsible for the generation of action potentials in nerves, skeletal muscles and the heart. Accordingly, Navs are the major targets for local anesthetic, antiepileptic and antiarrhythmic drugs. Recent structural studies using cryoelectron microscopy (cryo-EM) visualized various isoforms of Navs (Nav1.1, Nav1.2, Nav1.4, Nav1.5 and Nav1.7) at high[1]resolution. These studies have greatly advanced our understanding of channel architecture, voltage-sensing, fast inactivation, ion selectivity and channelopathy. The structures of Nav1.5, the primary Nav in the heart, have also been determined in a complex with class I antiarrhythmic drugs. Quinidine (Ia agent) and flecainide (Ic agent) interact with the key residue, F1760 on domain IV (DIV) S6 in the inactivated channel, but directly do not interact with Y1767. Although quinidine is engaged within the central cavity, flecainide is away from the central axis. On the other hand, propafenone (Ic agent) interacts with F1760 and Y1767 in the open channel. These three drugs are positioned right beneath the selectivity filter or the positively charged amino residues of these drugs which point toward the selectivity filter, and these drugs likely block the ion conduction pathway. Quinidine facilitates gate closing through an allosteric mechanism, but propafenone leaves the intracellular gate open. Although these studies reveal the accurate binding pose of these drugs in a single functional state, that is, the open or inactivated state of Nav1.5, it has been unknown what poses the drugs adopt state-dependently and isoform-dependently. Our previous structural modeling and docking of the mexiletine (Ib agent) in the open and resting or closed states of Nav1.5 showed that mexiletine occurs in the upper part in the pore in the open state and lower in the closed state. High-affinity binding of mexiletine in the open state of Nav1.5 is caused by a π-π interaction with F1760, whereas mexiletine is located away from the corresponding Phe (F1764) in the open state of Nav1.2, which has a lower affinity for mexiletine than Nav1.5. These structural observations of mexiletine block are consistent with the experimental data. This review will focus on the structural pharmacology of antiarrhythmic drug interactions with Nav1.5 and other Navs from the cryo-EM structures of Nav1.5 with the drugs, fenestrations forming hydrophobic pathways and the structural basis for isoform differences in the state-dependent block.
Bagnéris C, DeCaen PG, Naylor CE, Pryde DC, Nobeli I, Clapham DE, Wallace BA.
Prokaryotic NavMs channel as a structural and functional model for eukaryotic
sodium channel antagonism. Proc Natl Acad Sci U S A (2014) 111(23):8428-8433.
Boiteux C, Vorobyov I, Allen TW. Ion conduction and conformational flexibility of a
bacterial voltage-gated sodium channel. Proc Natl Acad Sci U S A (2014a)
111(9):3454-3459.
Boiteux C, Vorobyov I, French RJ, French C, Yarov-Yarovoy V, Allen TW. Local
anesthetic and antiepileptic drug access and binding to a bacterial voltage-gated
sodium channel. Proc Natl Acad Sci U S A (2014b) 111(36):13057-13062.
Camerino DC, Tricarico D, Desaphy JF. Ion channel pharmacology. Neurotherapeutics
(2007) 4:184-198.
Catterall WA. Cellular and molecular biology of voltage-gated sodium channels. Physiol
Rev (1992) 72(4 Suppl):S15-48.
Catterall WA. From ionic currents to molecular mechanisms: the structure and function of
voltage-gated sodium channels. Neuron (2000) 26(1):13-25.
Catterall WA, Goldin AL, Waxman SG. International Union of Pharmacology. XLVII.
Nomenclature and structure-function relationships of voltage-gated sodium channels.
Pharmacol Rev (2005) 57(4):397-409.
Catterall WA, Lenaeus MJ, Gamal El-Din TM. Structure and pharmacology of voltage gated sodium
and calcium channels. Annu Rev Pharmacol Toxicol (2020) 60:133-154.
Catterall WA, Wisedchaisri G, Zheng N. The conformational cycle of a prototypical
voltage-gated sodium channel. Nat Chem Biol (2020) 16(12):1314-1320.
Catterall WA, Zheng N. Deciphering voltage-gated Na+
and Ca2+ channels by studying
prokaryotic ancestors. Trends Biochem Sci (2015) 40(9):526-534.
Chabal C, Jacobson L, Mariano A, Chaney E, Britell CW. The use of oral mexiletine for
the treatment of pain after peripheral nerve injury. Anesthesiology (1992) 76(4):513-517.
DeMarco KR, Bekker S, Clancy CE, Noskov SY, Vorobyov I. Digging into lipid membrane
permeation for cardiac ion channel blocker d-sotalol with all-atom simulations. Front
Pharmacol (2018) 9:26.
Fozzard HA, Hanck DA. Structure and function of voltage-dependent sodium channels:
comparison of brain II and cardiac isoforms. Physiol Rev (1996) 76(3):887-926.
Gamal El-Din TM, Lenaeus MJ, Zheng N, Catterall WA. Fenestrations control resting-state
block of a voltage-gated sodium channel. Proc Natl Acad Sci USA (2018)
115(51):13111-13116.
Goldin AL. Mechanisms of sodium channel inactivation.
Curr Opin Neurobiol (2003) 13(3):284-90.
Hille B. Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor
reaction. J Gen Physiol (1977) 69(4):497-515.
Hodgkin AL, Huxley AF. A quantitative description of membrane current and its
application to conduction and excitation in nerve. J Physiol (1952) 117(4):500-44.
Hudson AJ, Ebers GC, Bulman DE. The skeletal muscle sodium and chloride channel
diseases. Brain (1995) 118:547-563.
Jackson CE, Barohn RJ, Ptacek LJ. Paramyotonia congenita: abnormal short exercise test,
and improvement after mexiletine therapy. Muscle Nerve (1994) 17:763-768.
Jiang D, Banh R, Gamal El-Din TM, Tonggu L, Lenaeus MJ, Pomès R, Zheng N, Catterall
WA. Open-state structure and pore gating mechanism of the cardiac sodium channel.
Cell (2021) 184(20):5151-5162.
Jiang D, Shi H, Tonggu L, Gamal El-Din TM, Lenaeus MJ, Zhao Y, Yoshioka C, Zheng
N, Catterall WA. Structure of the cardiac sodium channel.
Cell (2020) 180(1):122-134.
Lenaeus MJ, Gamal El-Din TM, Ing C, Ramanadane K, Pomès R, Zheng N, Catterall WA.
Structures of closed and open states of a voltage-gated sodium channel. Proc Natl
Acad Sci USA (2017) 114(15):E3051-E3060.
Li Z, Jin X, Wu T, Huang G, Wu K, Lei J, Pan X, Yan N. Structural basis for pore blockade
of the human cardiac sodium channel Nav 1.5 by the antiarrhythmic drug quinidine.
Angew Chem Int Ed Engl (2021a) 60(20):11474-11480.
Li Z, Jin X, Wu T, Zhao X, Wang W, Lei J, Pan X, Yan N. Structure of human Nav1.5
reveals the fast inactivation-related segments as a mutational hotspot for the long QT
syndrome. Proc Natl Acad Sci USA (2021b) 118(11):e2100069118.
Lipkind GM, Fozzard HA. Molecular modeling of local anesthetic drug binding by voltage
gated sodium channels. Mol Pharmacol (2005) 68:1611-1622.
McCusker EC, Bagnéris C, Naylor CE, Cole AR, D’Avanzo N, Nichols CG, Wallace BA.
Structure of a bacterial voltage-gated sodium channel pore reveals mechanisms of
opening and closing. Nat Commun (2012) 3:1102.
McNulty MM, Edgerton GB, Shah RD, Hanck DA, Fozzard HA, Lipkind GM. Charge at
the lidocaine binding site residue Phe-1759 affects permeation in human cardiac
voltage-gated sodium channels. J Physiol (2007) 581(2):741-755.
Nakagawa H, Munakata T, Sunami A. Mexiletine block of voltage-gated sodium channels:
Isoform- and state-dependent drug-pore interactions.
Mol Pharmacol (2019) 95(3):236-244.
Nau C, Wang SY, Strichartz GR, Wang GK. Point mutations at N434 in D1-S6 of mu1 Na+
channels modulate binding affinity and stereoselectivity of local anesthetic
enantiomers. Mol Pharmacol (1999) 56:404-413.
Nguyen PT, DeMarco KR, Vorobyov I, Clancy CE, Yarov-Yarovoy V. Structural basis for
antiarrhythmic drug interactions with the human cardiac sodium channel. Proc Natl
Acad Sci U S A (2019) 116(8):2945-2954.
Pan X, Li Z, Huang X, Huang G, Gao S, Shen H, Liu L, Lei J, Yan N. Molecular basis for
pore blockade of human Na+
channel Nav1.2 by the μ-conotoxin KIIIA. Science (2019)
363(6433):1309-1313.
Pan X, Li Z, Jin X, Zhao Y, Huang G, Huang X, Shen Z, Cao Y, Dong M, Lei J, Yan N.
Comparative structural analysis of human Nav1.1 and Nav1.5 reveals mutational
hotspots for sodium channelopathies. Proc Natl Acad Sci USA (2021)
118(11):e2100066118.
Pan X, Li Z, Zhou Q, Shen H, Wu K, Huang X, Chen J, Zhang J, Zhu X, Lei J, Xiong W,
Gong H, Xiao B, Yan N. Structure of the human voltage-gated sodium channel Nav1.4
in complex with β1. Science (2018) 362(6412):eaau2486.
Payandeh J, Gamal El-Din TM, Scheuer T, Zheng N, Catterall WA. Crystal structure of a
voltage-gated sodium channel in two potentially inactivated states. Nature (2012)
486(7401):135-139.
Payandeh J, Scheuer T, Zheng N, Catterall WA. The crystal structure of a voltage-gated
sodium channel. Nature (2011) 475(7356):353-358.
Ragsdale DS, McPhee JC, Scheuer T, Catterall WA. Molecular determinants of state
dependent block of Na+ channels by local anesthetics. Science (1994)
265(5179):1724-1728.
Ragsdale DS, McPhee JC, Scheuer T, Catterall WA. Common molecular determinants of
local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated Na+
channels. Proc Natl Acad Sci USA (1996) 93(17):9270-9275.
Shen H, Liu D, Wu K, Lei J, Yan N. Structures of human Nav1.7 channel in complex with
auxiliary subunits and animal toxins. Science (2019) 363(6433):1303-1308.
Shen H, Zhou Q, Pan X, Li Z, Wu J, Yan N. Structures of a eukaryotic voltage-gated sodium
channel at near-atomic resolution. Science (2017) 355(6328):eaal4326.
Stys PK, Lesiuk H. Correlation between electrophysiological effects of mexiletine and
ischemic protection in central nervous system white matter.
Neuroscience (1996) 71:27-36.
Sula A, Booker J, Ng LC, Naylor CE, DeCaen PG, Wallace BA. The complete structure of
an activated open sodium channel. Nat Commun (2017) 8:14205.
Sunami A, Dudley SC Jr, Fozzard HA. Sodium channel selectivity filter regulates
antiarrhythmic drug binding. Proc Natl Acad Sci USA (1997) 94(25):14126-14131.
Tao E, Corry B. Characterizing fenestration size in sodium channel subtypes and their
accessibility to inhibitors. Biophys J (2022) 121(2):193-206.
Tikhonov DB, Bruhova I, Zhorov BS. Atomic determinants of state-dependent block of
sodium channels by charged local anesthetics and benzocaine. FEBS Lett (2006)
580(26):6027-6032.
Tikhonov DB, Zhorov BS. Mechanism of sodium channel block by local anesthetics,
antiarrhythmics, and anticonvulsants. J Gen Physiol (2017) 149(4):465-481.
Wang GK, Quan C, Wang SY. Local anesthetic block of batrachotoxin-resistant
muscle Na+ channels. Mol Pharmacol (1998) 54:389-396.
Wang SY, Nau C, Wang GK. Residues in Na+
channel D3-S6 segment modulate both
batrachotoxin and local anesthetic affinities. Biophys J (2000) 79(3):1379-1387.
Weiser T, Qu Y, Catterall WA, Scheuer T. Differential interaction of R-mexiletine with the
local anesthetic receptor site on brain and heart sodium channel alpha-subunits. Mol
Pharmacol (1999) 56:1238-1244.
West JW, Patton DE, Scheuer T, Wang Y, Goldin AL, Catterall WA. A cluster of
hydrophobic amino acid residues required for fast Na+
-channel inactivation. Proc Natl
Acad Sci USA (1992) 89(22):10910-10914.
Wisedchaisri G, Tonggu L, McCord E, Gamal El-Din TM, Wang L, Zheng N, Catterall
WA. Resting-state structure and gating mechanism of a voltage-gated sodium channel.
Cell (2019) 178(4):993-1003.
Wright SN, Wang SY, Kallen RG, Wang GK. Differences in steady-state inactivation
between Na channel isoforms affect local anesthetic binding affinity. Biophys J (1997)
73(2):779-88.
Yan Z, Zhou Q, Wang L, Wu J, Zhao Y, Huang G, Peng W, Shen H, Lei J, Yan N. Structure
of the Nav1.4-β1 Complex from Electric Eel. Cell (2017) 170(3):470-482.
Yarov-Yarovoy V, Brown J, Sharp EM, Clare JJ, Scheuer T, Catterall WA. Molecular
determinants of voltage-dependent gating and binding of pore-blocking drugs in
transmembrane segment IIIS6 of the Na+
channel alpha subunit. J Biol Chem (2001) 276(1):20-27.
Yarov-Yarovoy V, McPhee JC, Idsvoog D, Pate C, Scheuer T, Catterall WA. Role of amino
acid residues in transmembrane segments IS6 and IIS6 of the Na+
channel alpha
subunit in voltage-dependent gating and drug block. J Biol Chem (2002)
277(38):35393-35401.
Zhang X, Ren W, DeCaen P, Yan C, Tao X, Tang L, Wang J, Hasegawa K, Kumasaka T,
He J, Wang J, Clapham DE, Yan N. Crystal structure of an orthologue of the NaChBac
voltage-gated sodium channel. Nature (2012) 486(7401):130-134.
We publish over 800 titles annually by leading researchers from around the world. Submit a Book Proposal Now!