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AnaLu ´ ciaS.Rodrigues
LaboratoryofNeurobiologyofDepression,DepartmentofBiochemistry,Centerof BiologicalSciences,FederalUniversityofSantaCatarina,Floriano ´ polis,SantaCatarina, Brazil
SusanSchenk
SchoolofPsychology,VictoriaUniversity,Wellington,NewZealand
GeraldSeifert
InstituteofCellularNeurosciences,MedicalFaculty,UniversityofBonn,Bonn,Germany
ChristianSteinha ¨ user
InstituteofCellularNeurosciences,MedicalFaculty,UniversityofBonn,Bonn,Germany
StephanieE.Titus
CenterforTranslationalPsychiatry,DepartmentofPsychiatryandBehavioralSciences, MedicalSchool,TheUniversityofTexasHealthScienceCenteratHouston,Houston, Texas,USA
TalitaTuon
LaboratoryofNeurosciences,GraduatePrograminHealthSciences,HealthSciencesUnit, UniversityofSouthernSantaCatarina,Criciuma,SantaCatarina,Brazil
Ya-JuanWang
CenterforProteomicsandBioinformaticsandDepartmentofEpidemiologyand Biostatistics,CaseWesternReserveUniversitySchoolofMedicine,Cleveland,Ohio,USA
MattiWeckstromw DivisionofBiophysics,DepartmentofPhysics,UniversityofOulu,OulunYliopisto, Finland
JohannesWeller
InstituteofCellularNeurosciences,MedicalFaculty,UniversityofBonn,Bonn,Germany
HongmeiWu
CollegeofLifeSciences,ShaanxiNormalUniversity,Xi’an,Shaanxi,PRChina
w MattiWeckstr€ omhasdied.
PREFACE
Ionchannelsarepore-formingmembraneproteinsexpressedinalmostall celltypes.Theseproteinstriggerelectricalsignalingthroughoutthebody bygatingtheflowofionsacrossthecellmembrane.Twocharacteristicfeaturesofionchannelsdistinguishthemfromothertypesofiontransporter proteins.First,thisistheveryhighrateofiontransportthroughthechannel comparedtoothertransporterproteins(often106 ionspersecondorgreater) andsecond,ionspassthroughchannelsdowntheirelectrochemicalgradient withouttheparticipationofmetabolicenergy.
Thesequencingofthehumangenomehasidentifiedmorethan400 putativeionchannels.However,onlyafractionofthesetheoreticallyidentifiedchannelshavebeenclonedandfunctionallycharacterized.Thewidespreadtissuedistributionofionchannels,alongwiththemultiple physiologicalconsequencesoftheiropeningandclosing,makestargeting ofionchannelsverypromisingtargetsfordevelopmentoftherapeutics. Thepotentialvalidationofionchannelsasdrugtargetsprovidesanenormousmarketopportunityfortheirreemergenceaskeytargetsindrugdiscovery.However,torealizethegreatpotentialofthistargetclass,an understandingofthevalidationofthesetargetsaswellasdevelopmentof suitablescreeningtechnologiesthatreflectthecomplexityofionchannel structureandfunctionremainskeydriversforexploitationofthis opportunity.
Inspiteofsomeimportantdrugstargetingionchannelswhicharetoday inclinicaluse,asaclass,ionchannelsremainunderexploitedindrugdiscovery.Furthermore,manyexistingdrugsarepoorlyselectivewithsignificant toxicitiesorsuboptimalefficacy.Thisthematicvolumeofthe Advancesin ProteinChemistryandStructuralBiology isdedicatedtoionchannelsastherapeutictargetsandmorespecificallyaspromisingtreatmenttargetsinneurologicalandpsychiatricdisorders.Chapter1inthisvolumesummarizes currentadvancesabouttheproteinbiogenesisprocessoftheCys-loop receptors.Operatingonindividualbiogenesisstepsinfluencesthereceptor cellsurfacelevel;thus,manipulatingtheproteostasisnetworkcomponents canregulatethefunctionofthereceptors,representinganemergingtherapeuticstrategyforcorrespondingchannelopathies.Chapter2proposesfor thefirsttimeanovelconceptualframeworkbindingtogethertransient receptorpotential(TRP)channels,voltage-gatedsodiumchannels(Nav),
technologyandbiomedicalknowledgesuggestthattheseproteinsarepromisingtargetsforfuturetherapeuticdevelopment.Therefore,theaimofthis volumeistopromotefurtherresearchinthestructure,function,andregulationofdifferentfamiliesofionchannelswhichwouldresultindesigning newefficienttargeteddrugswithsignificantlyfeweradverseeffects.
DR.ROSSEN DONEV BiomedConsultLtd
ProteostasisMaintenanceof Cys-LoopReceptors
Yan-LinFu*,Ya-JuanWang†,Ting-WeiMu*,1
*DepartmentofPhysiologyandBiophysics,CaseWesternReserveUniversitySchoolofMedicine,Cleveland, Ohio,USA
†CenterforProteomicsandBioinformaticsandDepartmentofEpidemiologyandBiostatistics,CaseWestern ReserveUniversitySchoolofMedicine,Cleveland,Ohio,USA
1Correspondingauthor:e-mailaddress:tingwei.mu@case.edu
Contents
1. Introduction2
2. Folding,Assembly,andDegradationofCys-LoopReceptorsintheER5
2.1 FoldingandAssemblyofCys-LoopReceptors5
2.2 ERADoftheCys-LoopReceptors
3. TraffickingofCys-LoopReceptorsfromERtoGolgiandtoPlasmaMembrane10
4. ProteinQualityControlofCys-LoopReceptorsonthePlasmaMembrane11
TheCys-loopreceptorsplayprominentrolesinthenervoussystem.Theyinclude γaminobutyricacidtypeAreceptors,nicotinicacetylcholinereceptors,5-hydroxytryptaminetype-3receptors,andglycinereceptors.Proteostasisrepresentsanoptimalstateof thecellularproteomeinnormalphysiology.Theproteostasisnetworkregulatesthe folding,assembly,degradation,andtraffickingoftheCys-loopreceptors,ensuringtheir efficientfunctionalcellsurfaceexpressions.Here,wesummarizecurrentadvancesabout theproteinbiogenesisprocessoftheCys-loopreceptors.Becauseoperatingonindividualbiogenesisstepsinfluencesthereceptorcellsurfacelevel,manipulatingthe proteostasisnetworkcomponentscanregulatethefunctionofthereceptors,representinganemergingtherapeuticstrategyforcorrespondingchannelopathies.
Figure1 StructuralcharacteristicsoftheCys-loopreceptors.(A)TheCys-loopreceptors arepentameric,formingacentralionpore.(B)EachsubunithasalargeERlumen domain,fourtransmembranehelices,andalargeintracellularloopdomain(ICD) betweenTM3andTM4.Thetwocysteinesthatformthesignaturedisulfidebondare showninspheremodel.ThecartoonsarebuiltfromthecrystalstructuresofGABAA receptors(4COF).
M3andM4isimportantformodulatingthetraffickingofthereceptorsand subunitclusteringoncellmembrane.Italsoaffectsthechannelconductance byinfluencingtheaccessibilityofthechannelporetoions(Thompson, Lester,&Lummis,2010).TheTMdomainsplayanimportantroleinchannelfolding,assembly,andgating.
ProteostasismaintenanceofCys-loopreceptorsensurestheirnormal functional(Balch,Morimoto,Dillin,&Kelly,2008).Theproteostasisnetworkregulatestheirfunctionalcellsurfaceexpressionlevelsbyoperatingon theirfolding,assembly,trafficking,anddegradationalongproteinbiogenesis pathways(Fig.2).Tofunction,individualsubunitsofCys-loopreceptors needtofoldintotheirnativestructuresandassemblecorrectlywithother subunitsintheendoplasmicreticulum(ER).Properlyassembledreceptors willbeabletobetransportedfromtheERthroughGolgitocellsurface. UnassembledsubunitsormisfoldedsubunitswillundergotheER-associated degradation(ERAD)pathway,beingretrotranslocatedintothecytosoland degradedbytheproteasome(Guerriero&Brodsky,2012;Olzmann, Kopito,&Christianson,2013;Smith,Ploegh,&Weissman,2011;Wang, Tayo,etal.,2014).Problemsinanystepduringthebiogenesisofthe Cys-loopreceptorsaffectthenormalsurfaceexpressionlevelofthereceptors,thuscausingdiseases.Forexample,manymutationsofhuman GABAARsleadtoepilepsybyabolishingthefolding,assembly,andtraffickingofthemutantreceptors(Macdonald,Kang,&Gallagher,2010).Also, thereceptorsonthecellsurfaceundergocontinuousendocytosisand
toreducedagonist-inducedcurrentsandamyotrophiclateralsclerosis (Richardsetal.,2011).TheS143L,C128S,andR147Lmutationslocated at N-terminalextracellulardomainof ε subunitsfornAChRsinfluencethe subunitassemblyandarelinkedtocongenitalmyasthenicsyndromes(Engel, Ohno, &Sine,1999).
Although itisessentialfortheCys-loopreceptorstoacquiretheircorrect foldingandassemblystatus,theseprocessesaredifficultbecauseeachreceptor,beingapentamer,hasalarge-molecularweight,whichisabout 250kDa,andeachsubunithasmultitransmembranedomains.Asaresult, theassemblyprocessisgenerallyinefficientandslow.Only25%ofnewly synthesizedGABAARsareassembledintoheteromericreceptors,and 30%ofthetranslated α subunitsofnAChRsareassembled(Gorrieetal., 1997; Wanamaker,Christianson,&Green,2003).Thehalf-lifeofthe nAChR assemblyismorethan90min,muchlongerthan7–10min,the half-lifeofinfluenzahemagglutinintoformhomotrimers(Wanamakeret al., 2003).TheGreengrouphasdeterminedtheassemblymodelsofnAChR by usingpulsechaseandcoimmunoprecipitationassayswithsubunits sequence-specificantibodies(Wanamakeretal.,2003).However,nofolding andassemblymodelsofotherCys-loopreceptorareavailableyet. TheassemblyofCys-loopreceptorsdependsontheN-terminalsignal. TheN-terminalextensionandputative α-helixinthe α1, β2,and γ2subunitsofGABAARsarerequiredfortheintersubunitassemblyandthuscan affectthecellsurfaceexpressionlevelofthereceptors(Wong,Tae,& Cromer, 2015).Also,N-terminalextensionand α-helix of ρ1GABAC receptors,whichalsobelongtoCys-loopreceptorfamily,arealsorequired forthenormalassembly,trafficking,andcellsurfaceexpressionofthereceptors(Wong,Tae,&Cromer,2014).Previousstudiesdeterminedthespecific amino acidslocatedattheN-terminusthatareimportantforthesubunit assemblyforGABAARs,nAChRs(Kreienkamp,Maeda,Sine,&Taylor, 1995; Sumikawa,1992;Sumikawa&Nishizaki,1994;Tsetlin,Kuzmin, &Kasheverov,2011),andGlyRs(Kuhse,Laube,Magalei,&Betz,1993; Tsetlin etal.,2011).However,theassemblyof5-HT3Rs(Connolly& Wafford, 2004),nAChRs(Avramopoulou,Mamalaki,&Tzartos,2004), GlyRs(Kuhseetal.,1993),butnotGABAARs(Buller,Hastings,Kirkness, & Fraser,1994),dependsonN-glycosylationstatusasallcys-loopchannels are glycoproteins.Inaddition,recentstudyshowedthatC-terminal motifsinnAChRsmayalsobeimportantforsubunitassembly(Lo, Botzolakis, Tang,&Macdonald,2008).Ahighlyconservedaspartateresidue at theboundaryoftheM3–M4loopandtheM4domainisrequiredfor
Phosphorylationof α4-nAChRsubunitsataproteinkinaseA(PKA)consensussequenceenhancestheinteractionof14-3-3proteinstothe α4subunitsintheERandpromotestheassemblyofcomplete α4β2-nAChRs (Bermudez&Moroni,2006).
3.TRAFFICKINGOFCYS-LOOPRECEPTORSFROMERTO GOLGIANDTOPLASMAMEMBRANE
Golgi-specificDHHC(Asp-His-His-Cys)zincfingerprotein (GODZ),whichbelongstoDHHCfamilypalmitoylacyltransferase,specificallypalmitoylatesthe γ2subunitsofGABAARs.Thepalmitoylationis requiredfortargetingthereceptorstoinhibitorysynapses.Knockdownof GODZcausesthelossofGABAARs,thusleadingtoreducedGABAARmedicatedminiatureinhibitorysynapticcurrentamplitudeandfrequency (Fangetal.,2006;Kelleretal.,2004;Luscheretal.,2011).
The brefeldinA-inhibitedGDP/GTPexchangefactor2(BIG2)interactswiththeICDof β subunitsofGABAARs.Itenhancesthetraffickingof β3-containingGABAARsbypromotingthemembranebuddingofvesicles fromGolgiapparatus(Shin,Morinaga,Noda,&Nakayama,2004).
The GABAAR-associatedprotein(GABARAP),whichbelongstoa ubiquitin-likefamilyproteininmammalsandisenrichedinGolgiand othersomatodendriticmembranecompartments,facilitatesthetrafficking ofGABAARsinhippocampusneuronontoplasmamembranethrough connectingthe γ subunitswithmicrotubules(Nymann-Andersenetal., 2002; Wang,Bedford,Brandon,Moss,&Olsen,1999).ThisGABARAP effect alsodependsontheinteractionofphospholipidstoGABARAP (Chen,Chang,Leil,&Olsen,2007).
Phospholipase C-relatedcatalyticallyinactiveprotein(PRIP)isinositol1,4,5-trisphosphate-bindingproteins.Itmayserveasabridgeprotein whichconnects γ2-containingGABAARswithGABARAPandpromotes thetraffickingofthereceptors.InterruptingtheinteractionofPRIP with γ2subunitsofGABAARsdecreasesthesurfaceexpressionlevelof thereceptorsinbothculturedcelllinesandneurons(Mizokamietal., 2007).
VILIP-1, aneuronalprotein,enhancesthesurfaceexpressionof α4β2nAChRsinhippocampalneuronsbypromotingtheirexitfromthetransGolginetwork.ThiseffectisactivatedbyincreasingintracellularCa2+ Asaresult,itisanimportantfactorthatmediatestheneuronactivityinducedsurfaceexpressionlevelchangeofthereceptors(Zhaoetal.,2009).
ProteinUnc-50,whichisfoundinnematode C.elegans butevolutionarilyconserved,isneededforthetransportofspecifictypesofnAChRsonto thecellsurfacewithunknownmechanism(Eimeretal.,2007).
4.PROTEINQUALITYCONTROLOFCYS-LOOP RECEPTORSONTHEPLASMAMEMBRANE
4.1Clustering
RestrictionofCys-loopreceptorstodesignatedsitesonthepostsynaptic plasmamembraneisalsotightlyregulated.Thisprocessisimportantfor shapingthepostsynapticsitestypesandregulatingthereceptors-mediated inhibitoryorexcitatoryeffect.
GephyrinregulatestheclusteringofGlyRsandGABAARs.Gephyrinis ascaffoldproteinthatmainlyaccumulatesininhibitoryGABAergicand glycinergicsynapsesinvariousbrainregions.Glycinereceptorswerethefirst tobefounddependingongephyrintoclusteratpostsynapticsites.Glycerine β loopinteractswithEdomainofgephyrin.Gephyrinisalsoinvolvedinthe intracellulartraffickingandlateralmovementofglycinereceptors(Fritschy, Harvey, &Schwarz,2008).Gephyrin-inducedclusteringofGABAARsis subunit-specific.Gephyrinknockoutinmicediminishesthenumberof α2, α3, β2/3,and γ2subunits-containingsynapticsites,butnotthe α1-, α5-containingsynapticsiteswithoutaffectingthenumberoftotalinhibitory synapticsites(Jacob,Moss,&Jurd,2008).Thiscouldbeduetothefactthat there areonlycertaintypesofGABAARsubunitsthatcanassociatewith gephyrin.GephyrinEdomainassociateswitha10-aminoacidhydrophobic motifwithintheintracellulardomainoftheGABAAR α2, α3,andgephyrin alsointeractsweaklywith γ2,and β3subunits(Kneusseletal.,2001;Tretter et al.,2008).Gepyrinisalsoimportantinregulatingtheneuronactivityplasticity. Long-terminhibitorypotentiationofneuronsinvisualcortex increasesGABAAR-mediatedinhibitorypostsynapticcurrentsbyinducing theCaMKIIphosphorylationoftheGABAAR β3S383 residueandenhances gephyrinclusteringof β3-containingGABAARs.PhosphorylationdependentinteractionofPin,apeptidyl-prolylisomerase,withgephyrin modulatesgephyrininteractionwithglycinereceptorsandthustheirclustering(Fritschyetal.,2008).Collybistin,aguanidineexchangefactoractivating cdc-42, formsabindingcomplexwithgephyrin.Knockoutofcollybistinin micedoesnotaffectglycinergicsynaptictransmissionbutdecreases GABAergicsynaptictransmission.Collybistinisnotrequiredfor gephyrin-mediatedGlyRclusteringbutnecessaryforgephyrin-mediated
(Chen&Olsen,2007).Membranesphingolipidsandotherlipidspromote the surfaceexpressionlevelofmuscle-typenAChRsbyaffectingthebiosynthesisprocessinER(Baier&Barrantes,2007).Decreasingthemembrane cholesterol promotestheendocytosisofnAChRsanddecreasestheircell expressionlevel(Borronietal.,2007).Theunderlyingmechanismisthat membrane lipidservesaslipidrafts,whichisrequiredforthetrafficking andmembranestabilizationofthereceptors.
5.2PhosphorylationSignalingintheBiogenesisofthe Receptors
PhosphorylationaffectstheCys-loopreceptorchannelproperties(Swope, Moss, Raymond,&Huganir,1999)andmodulatestheefficacyofreceptor-mediated effectbyinfluencingtheirtrafficking,endocytosis,and recyclingprocess.Neuronalactivitiesthatleadtothechangeintheintracellularcalciumsignalregulatetheactivityofkinasesandphosphatases, resultinginthealteredthebiogenesisprocessandthusthesurfaceexpression levelofthereceptors.Forexample,enhancedexcitatorysynapticactivities activatephosphatasecalcineurinthroughCa2+/calmodulinpathway followedbyanincreaseinintracellularCa2+ concentration.ActivatedcalcineurindephosphorylatesSer327intheGABAAR γ2subunit,whichleads totheenhancedlateralmobilityofthereceptors,decreasedclustersizeof GABAARs,andreducedGABAergicmIPSC(Bannaietal.,2009).Calcineurin isalsoinvolvedindownregulationofthe α2-containingGABAAR membraneexpressionlevelinprolongedseizuresactivitylinkedtobenzodiazepinepharmacoresistance(Eckel,Szulc,Walker,&Kittler,2015). PRIP, asmentionedabove,modulatestheGABAARsurfaceexpression levelbyaffectingthephosphorylationofthereceptors.PRIPinactivates theproteinphosphatase1α (PP1α),whichdephosphorylatestheGABAARs phosphorylatedbyPKA.Asaresult,PRIPpositivelyregulatesthereceptor surfaceexpressionandreceptor-mediatedinhibitioneffectinhippocampal neuron(Kittler&Moss,2003;Terunumaetal.,2004;Yoshimuraetal., 2001).
Many neurosteroidsorneurotrophicfactorsregulatethesurfaceexpressionlevelofreceptorbyaffectingthetrafficking,endocytosis,andrecycling process.Forexample,neurosteroidspromotethePKCphosphorylationof α4subunitSer443site,whichenhancestheinsertionofthe α4subunitcontainingGABAARsandleadstoincreasedtonicinhibition(Abramian et al.,2010).However,thesameneurosteroiddoesnothaveanyeffecton the α1-and α5-containingGABAARs,whichmediatethephasicinhibition
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