Review series introduction

The channelopathies: novel insights into molecular and genetic mechanisms of human disease
Robert S. Kass
Department of Pharmacology, Columbia University Medical Center, New York, New York, USA.

Ion channels are pore-forming proteins that provide pathways for the controlled movement of ions into or out of cells. Ionic movement across cell membranes is critical for essential and physiological processes ranging from control of the strength and duration of the heartbeat to the regulation of insulin secretion in pancreatic cells. Diseases caused by mutations in genes that encode ion channel subunits or regulatory proteins are referred to as channelopathies. As might be expected based on the diverse roles of ion channels, channelopathies range from inherited cardiac arrhythmias, to muscle disorders, to forms of diabetes. This series of reviews examines the roles of ion channels in health and disease.
Introduction Ionchannelsareadiversegroupofpore-formingproteinsthat crossthelipidmembraneofcellsandselectivelyconductions acrossthisbarrier.Ionchannelscoordinateelectricalsignalsin mosttissuesandarethusinvolvedineveryheartbeat,everymovement,andeverythoughtandperception.Theyhaveevolvedto selectivelyprovidepathwaysforionstomovedowntheirelectrochemicalgradientsacrosscellmembranesandeitherdepolarize cells,bymovingpositivelychargedionsin,orrepolarizecells,by movingpositivelychargedionsout. Duringthepast50years,ourunderstandingoftherolesand molecularstructureofionchannelshasgrownatarapidpaceand hasbridgedfundamentalbasicresearchwithadvancesinclinical medicine.Thelinkbetweenbasicscienceandclinicalmedicinehas beenthediscoveryofhumandiseaseslinkedtomutationsingenes codingforionchannelsubunitsorproteinsthatregulatethem: thechannelopathies. Ion channels: from squid giant axons to atomic structure Before1982,insightintomechanismsunderlyingtheionicbasis ofelectricalactivityinexcitablecellswaslimitedtomodelsystems. Ourunderstandingofthesemechanismswasbasedlargelyonthe beautifulworkofHodgkin,Huxley,andCole,amongothers,who unraveledtheionicbasisofnerveexcitationinthesquidgiant axon(14)andsubsequentlyshowedthatsimilarmechanisms wereresponsibleforexcitationandcontractionofamphibian skeletalmuscle(5).Usingmammalianpreparations,othergroups soondemonstratedsimilar,thoughmorecomplex,mechanisms underlyingelectricalactivityintheheart(6).However,thelink betweenmechanismsinthesemodelsystemsandhumanphysiologyremainedindirect.Thischangeddramaticallyin1982when thefirstionchannel,acetylcholinereceptor-subunit,wascloned (7,8).Molecularbiologyprovidedthetechniquestoidentifygenes encodingionchannels,and,asaresult,aplethoraofchannelshas beendiscoveredtobecriticaltothephysiologicalfunctionofvirNonstandard abbreviations used:LQTS,longQTsyndrome. Conflict of interest:Theauthorhasdeclaredthatnoconflictofinterestexists. Citation for this article:J. Clin. Invest.115:19861989(2005). doi:10.1172/JCI26011.
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tuallyeverytissue,controllingsuchdiversefunctionsashearing andinsulinsecretion.Thecombinationofgeneticidentification ofmultiplechannelgenesandthedevelopmentofpatch-clamp electrophysiologicalproceduresbyNeherandSakmann(9)made itpossibletoanalyzeingreatdetailthefunctionalpropertiesof ionchannelsinsmallcells,eliminatingtherestrictiontomodel systemsandextendingunderstandingoftherolesofmolecular structuresinthecontrolofchannelfunction. Thecrystalstructureofabacterialpotassiumchannelwassolved in1998(10),revealing,attheatomiclevel,thestructuralbasisof fundamentalmechanismsofthisclassofionchannels.Insight intochannelstructureclarifiedthemannerinwhichthechannels openandclose;thestructuralbasisforselectionofionsthatcan passthroughtheopenchannelpore;andthemechanismbywhich thechannelproteinssensechangesintransmembranevoltagethat controltheopenorclosedconformationalstatesofthechannel (Figure1)(11).Thusinvestigationsofionchannelproteinsbridge fundamentalphysicswithfunctionofbiologicallycriticalproteins.Butthelinktohumandiseasehascomefromclinicalinvestigationsofcongenitaldisordersandthediscoveriesthatdefects ingenescodingforionchannelsorionchannelregulatorysubunitscausediversediseasestates.Thenumberofdiseaseslinked tothesemutationsissolargethatthetermchannelopathyhas beenintroducedtodefinethisclassofdisease(Table1). InthisissueoftheJCI,wehaveassembledaseriesofreview articlestoprovidethemostup-to-dateinformationonchannelopathiesandtoassesshowinvestigationsofthesedisordershave increasedourunderstandingofthemechanismsofhumandisease. Ratherthanservingasanextensivecatalogofallchannelopathies, thesepapersimpartbothahistoricalperspectiveandanopportunitytounderstandhowmutationsthatcausecommonchanges inionchannelfunctionmaybeassociatedwithdiversediseases dependingonthetissuesinwhichthechannelsareexpressed. Sodium channels ThechannelopathiesareintroducedbyA.L.GeorgeJr.withabroad discussionoftheimpactofmutationsofvoltage-gatedsodiumchannelsonhumandisease(12).Mutationsingenescodingforsodium channelsarenowknowntocausenearly20disordersrangingfrom skeletalmuscledefectstodysfunctionofthenervoussystem(12).

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Figure 1
Inherited mutations alter ion channel function and structure and cause human disease. Mutations may alter the permeation pathway (A) to inhibit the movement of ions through an open channel pore and may also alter ion channel gating by changing either the process by which channels open (activate) (B) or the process by which they inactivate (C). Transitions from the open to the inactivated state reduce the number of channels that are available to conduct ions. Mutations that destabilize the inactivated, nonconducting state of the channel are gain-of-function mutations and are common to diverse diseases, including LQTS, certain forms of epilepsy, and muscle disorders such as hyperkalemic paralysis.

Investigationintothefunctionalconsequencesofthesemutations inheterologousexpressionsystemshasrevealednovelmechanisms underlyingdiseaseprocesses(1315),mutation-specifictherapeuticapproachestodiseasemanagement(16,17),and,importantly, commonfunctionalmechanismsunderlyingsuchdiversediseases ascardiacarrhythmiasandseizuredisorders(12,18). Sodiumchannelsopeninresponsetomembranedepolarization and,whileopen,providethepathwayfortheinwardmovement ofpositivelychargedsodiumions.Thisresultsinaregenerative processthatisnecessaryforconductionofelectricalimpulsesin nerveandmuscle.Withinmillisecondsofopening,mostvoltagegatedsodiumchannelsenteranonconductinginactivatedstate. Therapidtransitionfromopentoinactivatedstatesisnecessaryto controldurationsofelectricalimpulsesinalltissues.Mostinheritedsodiumchannelmutationsthatareassociatedwithhuman diseasealtertheinactivationprocessandhencealtertheessential controlofelectrical-impulsedurationthatiseffectedbytransitionsintotheinactivatedstate.Analysisofskeletalmuscledisordersidentifiedsomeofthefirstchannelopathiesassociatedwith mutationsthataltersodiumchannelinactivation.Inthisreview series,Jurkat-RottandLehmann-Horndescribetheseandother skeletalmusclechannelopathies(19).Theseauthorsprovidean overviewoftherolesofsodiumchannelsinmusclephysiology andexplainhowmutationsthatalterchannelinactivationmay resultintheclinicalpathologiesandmyotonias.Theynotethatin Na+channelmyotoniaandparamyotonia,mutation-inducedgatingdefectsoftheNa+channelsdestabilizetheinactivatedstateof

thechannelsuchthatinactivationmaybeslowedorincomplete. Thisresultsinhyperexcitability,repetitivemusclestimulation,and fatigue(19).Acriticaldiscussionofmusclechannelopathiesthat maybecausedbymutationsinotherionchannelgenes,byantibodiesdirectedagainstionchannelproteins,orbychangesofcell homeostasisleadingtoaberrantsplicingofionchannelRNAorto disturbancesofmodificationandlocalizationofchannelproteins isalsopresented(19). Theimportanceofmutation-alteredsodiumchannelinactivationtohumandiseaseisfurtherexploredbyMeislerandKearney (20),whopresentadetaileddiscussionoftherolesofsodiumchannelmutationsinepilepsyandotherseizuredisorders.Theypoint outthatsincethefirstmutationsoftheneuronalsodiumchannelSCN1Awereidentified5yearsago,morethan150mutations havebeendescribedinpatientswithepilepsy,andtheysuggest thatsodiumchannelmutationsmaybesignificantfactorsinthe etiologyofnumerousneurologicaldiseasesandmaycontribute topsychiatricdisordersaswell.Interestingly,mutationsrelated toepilepsypredominantlyaffectsodiumchannelinactivation.In thesecases,defectiveinactivationofthechannelscouldcontributetohyperexcitability.Thussimilarchannelmutationsmayhave diverseandmarkedlydifferentclinicalconsequencesdepending onthetissueinwhichthechannelisexpressed. Long QT syndrome LongQTsyndrome(LQTS),araregeneticdisorderassociatedwith life-threateningarrhythmias,isnextreviewedbrieflybyMossand Kass(21).LQTSinvestigationshaveprovidedfundamentalnew insightintothemolecularandgeneticbasisofelectricalsignaling intheheart.Todate,mutationsinatleast8differentgeneshave beenassociatedwithLQTS.ThemostprevalentLQTSgenescode forionchannelsubunits,butregulatoryproteinsarealsoassociatedwiththisdisorder.ThoughLQTSiscausedbyadiversegroupof genes,thecommonclinicalphenotypeisdelayedventricularrepolarization,which,inmostcases,iscausedbymutation-induced lossofpotassiumchannelfunctionoragainofsodiumchannel function.Themutation-alteredchannelfunctionthatunderlies LQTSisremarkablysimilartoalteredchannelfunctioninepilepsy andskeletalmuscledisorders,andthissimilarityprovidesinsight intothephysiologicallyessentialbalanceofionchannelfunction indiversecellsandtissue. AnimportantcontributionofLQTSinvestigationsdiscussedby MossandKasshasbeenthediscoverynotonlyofmutation-specificriskfactorsfordifferentgeneticvariantsofLQTS(22,23)but ofmutation-specifictherapeuticstrategiestomanagethedisorder (16,24).Becausetheclinicalphenotype,prolongedQTintervalon theECG,isdeterminedbyroutinenoninvasiveprocedures,LQTS
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Table 1 Selected channelopathies reviewed in this series
Protein Nav1.1 Nav1.2 Nav1.4 Nav1.5 SCN1B KCNQ1 KCNH2 Kir2.1 HERG Gene SCN1A SCN2A SCN4A SCN5A SCN1B KCNQ1 KCNH2 KCNJ2 KCNH2 Disease Generalized epilepsy with febrile seizures plus (GEFS+) Generalized epilepsy with febrile and afebrile seizures Paramyotonia congenita, potassium-aggravated myotonia, hyperkalemic periodic paralysis LQTS/Brugada syndrome Generalized epilepsy with febrile seizures plus (GEFS+) Autosomal-dominant LQTS with deafness Autosomal-recessive LQTS LQTS LQTS with dysmorphic features Congenital and acquired LQTS LQTS Timothy syndrome Persistent hyperinsulinemic hypoglycemia of infancy Diabetes mellitus Persistent hyperinsulinemic hypoglycemia of infancy Dilated cardiomyopathy Autosomal-dominant LQTS with deafness Autosomal-dominant LQTS LQTS Cystic fibrosis Myotonia (autosomal-recessive or -dominant) Dent disease Osteopetrosis (recessive or dominant) Bartter syndrome type III Central core disease, malignant hyperthermia Catecholaminergic polymorphic tachycardia Functional defect Hyperexcitability Hyperexcitability Hyperexcitability Heart action potential Hyperexcitability Heart action potential/inner ear K+ secretion Heart action potential Heart action potential Heart action potential Heart action potential and excessive responses to drugs Heart action potential Multisystem disorders Insulin hypersecretion Insulin hyposecretion Insulin hyposecretion Metabolic signaling Heart action potential Heart action potential Heart action potential Epithelial transport defect Defective muscle repolarization Defective endosome acidification Defective bone resorption Renal salt loss Abnormal muscle activity Exercise-related cardiac arrhythmias Reference 12, 20 12, 20 12, 19, 20 21 12, 20 21 21 21 21, 26 21 21 29 29 29 21 21 28 19, 28 28 28 28 19, 27 27

Ankyrin-B ANKB Cav1.2 CACNA2 Kir6.2 KCNJ11 SUR1 SUR2 KCNE1 KCNE2 CFTR ClC-1 ClC-5 ClC-7 ClC-Kb RyR1 RyR2 SUR1 SUR2 KCNE1 KCNE2 ABCC7 CLCN1 CLCN5 CLCN7 CLCNKB RyR1 RyR2

hasledtofundamentallynovelunderstandingoftheprocesses thatcontrolandregulateelectricalactivityintheheart. Drug-inducedQTprolongationdefinesacquiredLQTS(25). Though, by definition, this disorder is not due to mutationinducedQTprolongationduedirectlytochangesinionchannel geneproducts,considerableevidenceindicatesthat,inmanycases, variationsinionchannelgenesthatarenotsufficientlysevereto beclassifiedasmutations,butinsteadarereferredtoaspolymorphisms,maycontributetouniquedrugresponsesincarriersof thesegenevariants.Drug-inducedQTprolongation,so-called acquiredLQTS,isreviewedbyRodenandViswanathan(26). Ion channels in cellular organelles and nonexcitable cells Ionchannelsexpressedinplasmamembranesaffectcellularexcitabilityinnerveandmuscle,butexpressionofionchannelsinnonexcitablecellsandmembranesofintracellularorganellessuchas thesarcoplasmicreticulum,lysosomes,andmitochondriaconfersa broadrangeoffunctionalrolestotheseimportantproteins.Mutationsinchannelsresponsibleforthecontrolofintracellularcalciumreleasefromtheprincipalintracellularcalciumstoreinmuscle, thesarcoplasmicreticulum,haveonlyrecentlybeendiscoveredto underlieaclassofintracellularcalciumdependentarrhythmias anddisorders.PrioriandNapolitanoreviewthecurrentknowledge aboutthemutationsofthegeneencodingthecardiacryanodine receptor(RyR2)thatcausecardiacarrhythmias(27).Theseauthors discussthesimilaritiesbetweenthemutationsidentifiedingenes
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codingforcalciumreleasechannels(ryanodinereceptors).Inthe heart,mutationsintheryanodinereceptorRyR2causecardiac arrhythmias.Inskeletalmuscle,mutationsintheryanodinereceptorRyR1causemalignanthyperthermiaandcentralcoredisease. Finally,reviewsbyJentschetal.(28)andAshcroft(29)concentrateonchannelopathiesinclassicallynonexcitabletissue.Jentsch etal.(28)focusondiseasesrelatedtotransepithelialtransportand ondisordersinvolvingvesicularClchannels.Asispointedout intheirreview,thetransportofanionsacrosscellularmembranes iscrucialformultiplephysiologicalfunctionsthatincludethe controlofelectricalexcitabilityofmuscleandnerve,transportof saltandwateracrossepithelia,andtheregulationofcellvolume ortheacidificationandionichomeostasisofintracellularorganelles.Consequently,mutationsinClchannelsareassociatedwith diversehumandisease. ATP-sensitivepotassium(KATP)channels,sonamedbecausethey areinhibitedbyintracellularATP,couplecellmetabolismtoelectricalactivityoftheplasmamembrane.WhenintracellularATP concentrationsfall,thesechannelsopenandhyperpolarizecells. Conversely,whenintracellularATPconcentrationsareelevated, KATPchannelsclose,resultinginmembranedepolarization.In pancreaticcells,membranedepolarizationinducedbyclosureof thesechannelsresultsinactivationofvoltage-dependentcalcium channelsand,consequently,glucose-dependentinsulinsecretion.Thus,KATPchannelsserveastargetsfordrugsthatareused totreatandcontroltype2diabetes,suchasthesulphonylureas. ThereviewbyAshcroft(29)highlightsinsulinsecretorydisorders,

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suchascongenitalhyperinsulinemiaandneonataldiabetes,that resultfrommutationsinKATPchannelgenesandconsiderswhetherdefectiveregulationofKATPchannelactivitycontributestothe etiologyoftype2diabetes. Summary TheaimofthisspecialJCIseries onchannelopathiesistoreview selecteddisorderscausedbymutationsthatresultindefectiveion channelfunction,regulation,orexpression.Together,thiscollectionofarticlesillustratestheimpactthatinvestigationofthese diseaseshashadonourunderstandingofthemechanisticbasisof humandisease,revealingcriticalrolesofionchannelfunctionin physiologicalprocessesasdiverseasmuscleactivationandregula 1.Hodgkin,A.L.,andHuxley,A.F.1952.Aquantitativedescriptionofmembranecurrentandits applicationtoconductionandexcitationinnerve. J. Physiol. 117:500544. 2.Hodgkin,A.L.,andRushton,W.A.H.1946.The electricalconstantsofacrustaceannervefiber. Proc. R. Soc. Lond. B.B133:444479. 3.Hodgkin,A.L.,andHuxley,A.F.1952.Propagation ofelectricalsignalsalonggiantnervefibers.Proc. R. Soc. Lond. B Biol. Sci.140:177183. 4.Cole,K.S.1979.Mostlymembranes(KennethS. Cole).Annu. Rev. Physiol.41:124. 5.Hodgkin,A.L.,andHorowicz,P.1959.Movements of Na and K in single muscle fibres. J. Physiol. 145:405432. 6.Weidmann,S.1952.Theelectricalconstantsof Purkinjefibres.J. Physiol.118:348360. 7.Noda,M.,etal.1982.PrimarystructureofalphasubunitprecursorofTorpedocalifornicaacetylcholinereceptordeducedfromcDNAsequence. Nature.299:793797. 8.Giraudat,J.,Devillers-Thiery,A.,Auffray,C.,Rougeon,F.,andChangeux,J.P.1982.Identificationof acDNAclonecodingfortheacetylcholinebindingsubunitofTorpedomarmorataacetylcholine receptor.EMBO J.1:713717. 9.Neher,E.,andSakmann,B.1976.Single-channel currentsrecordedfrommembraneofdenervated frogmusclefibres.Nature.260:799802. 10.Doyle,D.A.,etal.1998.Thestructureofthepotassiumchannel:molecularbasisofK+conduction andselectivity.Science.280:6977. 11.MacKinnon,R.2003.Potassiumchannels.FEBS

tionofinsulinsecretion.Remarkableconservationoftheessential functionofionchannelsemergesfromthisseriesofreviewarticles inthisissueoftheJCIfunctionthat,whendisruptedinneurons, maycauseepilepsy,but,whendisruptedintheheart,causesfatal cardiacarrhythmias.Thelessonsfromthesestudiesaredramatic andclearlycallforadditionalcollaborativeinvestigationinwhich clinicalandpreclinicalscientists,workingtogether,continueto unravelthemolecularbasisofdiversehumandisorders. Addresscorrespondenceto:RobertS.Kass,DepartmentofPharmacology,ColumbiaUniversityMedicalCenter,630West168th Street,PH7W318,NewYork,NewYork10032,USA.Phone:(212) 305-7444;Fax:(212)305-8780;E-mail:rsk20@columbia.edu.
doi:10.1172/JCI25466. 21.Moss,A.J.,andKass,R.S.2005.LongQTsyndrome: fromchannelstocardiacarrhythmias.J. Clin. Invest. 115:20182024.doi:10.1172/JCI25537. 22.Moss,A.J.,etal.2002.Increasedriskofarrhythmic eventsinlong-QTsyndromewithmutationsinthe poreregionofthehumanether-a-go-go-related genepotassiumchannel.Circulation.105:794799. 23.Schwartz,P.J.,etal.2001.Genotype-phenotypecorrelationinthelong-QTsyndrome:gene-specific triggersforlife-threateningarrhythmias.Circulation.103:8995. 24.Moss,A.J.,etal.2000.Effectivenessandlimitations ofbeta-blockertherapyincongenitallong-QTsyndrome.Circulation.101:616623. 25.Fenichel,R.R.,etal.2004.Drug-inducedtorsades depointesandimplicationsfordrugdevelopment. J. Cardiovasc. Electrophysiol.15:475495. 26.Roden,D.M.,andViswanathan,P.C.2005.GeneticsofacquiredlongQTsyndrome.J. Clin. Invest. 115:20252032.doi:10.1172/JCI25539. 27.Priori,S.G.,andNapolitano,C.2005.Cardiacand skeletalmuscledisorderscausedbymutationsin theintracellularCa2+releasechannels.J. Clin. Invest. 115:20332038.doi:10.1172/JCI25664. 28.Jentsch,T.J.,Maritzen,T.,andZdebik,A.A.2005. Chloridechanneldiseasesresultingfromimpaired transepithelial transport or vesicular function.J. Clin. Invest.115:20392046.doi:10.1172/ JCI25470. 29.Ashcroft, F.M. 2005. ATP-sensitive potassium channelopathies:focusoninsulinsecretion.J. Clin. Invest.115:20472058.doi:10.1172/JCI25495.

Lett.555:6265. 12.George, A.L., Jr. 2005. Inherited disorders of voltage-gated sodium channels. J. Clin. Invest. 115:19901999.doi:10.1172/JCI25505. 13.Clancy,C.E.,Tateyama,M.,Liu,H.,Wehrens,X.H., andKass,R.S.2003.Non-equilibriumgatingin cardiacNa+channels:anoriginalmechanismof arrhythmia.Circulation.107:22332237. 14.Clancy,C.E.,andKass,R.S.2005.Inheritedand acquiredvulnerabilitytoventriculararrhythmias: cardiacNa+andK+channels.Physiol. Rev.85:3347. 15.Nuyens,D.,etal.2001.Abruptrateaccelerations orprematurebeatscauselife-threateningarrhythmiasinmicewithlong-QT3syndrome.Nat. Med. 7:10211027. 16.Benhorin,J.,etal.2000.Effectsofflecainidein patientswithnewSCN5Amutation:mutationspecifictherapyforlong-QTsyndrome?Circulation. 101:16981706. 17.Abriel,H.,Wehrens,X.H.,Benhorin,J.,Kerem,B., andKass,R.S.2000.Molecularpharmacologyof thesodiumchannelmutationD1790Glinkedto thelong-QTsyndrome.Circulation.102:921925. 18.Lossin,C.,Wang,D.W.,Rhodes,T.H.,Vanoye,C.G., andGeorge,A.L.,Jr.2002.Molecularbasisofan inheritedepilepsy. Neuron. 34:877884. 19.Jurkat-Rott,K.,andLehmann-Horn,F.2005.Musclechannelopathiesandcriticalpointsinfunctionalandgeneticstudies.J. Clin. Invest.115:20002009. doi:10.1172/JCI25525. 20.Meisler, M.H., and Kearney, J.A. 2005. Sodium channelmutationsinepilepsyandotherneurological disorders. J. Clin. Invest. 115:20102017.

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