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Smartox/BDS-I是Kv3.4的选择性阻断剂和有效的Nav1.7活化剂/BDS001-00100/0.1mg
BDS-1isa43aminoacidpeptidewhichwasoriginallyisolatedfromthevenomoftheseaanemonaAnemoniaViridis.BDS-1wasoriginallydescribedasahighlyselectiveblockeroftherapidlyinactivatingvoltage-gatedpotassiumchannelKv3.4/KCNC4,apotentialtherapeutictargetformajorCNSdisorders(AlzheimerandParkinsondiseases).Thetoxinactsasgatingmodifiers,mainlybyshiftingthevoltage-dependenceofactivation.Channelblockoccurswithhighaffinity(IC50of43nM)andisrapidandreversIBLe.BDS-1alsoblockstheKv3.1andKv3.2channelsalbeitwithaloweraffinity(>200nM).Finally,inamorerecentstudy,itwasdemonstratedthatBDS-1isaselectivegatingactivatoroftheNav1.7channelsubtype,animportanttargetforpainmanagement.Onthehumanisoform,modulationiswitnessedbyadrasticslowingofchannelinactivationwhichoccurswithanIC50of3nM.
Description:
AAsequence:Ala-Ala-Pro-Cys4-Phe-Cys6-Ser-Gly-Lys-Pro-Gly-Arg-Gly-Asp-Leu-Trp-Ile-Leu-Arg-Gly-Thr-Cys22-Pro-Gly-Gly-Tyr-Gly-Tyr-Thr-Ser-Asn-Cys32-Tyr-Lys-Trp-Pro-Asn-Ile-Cys39-Cys40-Tyr-Pro-His-OH
Disulfidebonds: Cys4-Cys39,Cys6-Cys32,Cys22-Cys40
Length(aa):43
Formula: C210H297N57O56S6
Appearance:Whitelyophilizedsolid
MolecularWeight:4708.37Da
CASnumber:
Source:Synthetic
Solubility:Waterorsalinebuffer
Reference:
SeaanemonepeptideswithaspecificblockingactivityagainstthefastinactivatingpotassiumchannelKv3.4
Seaanemonevenomisknowntocontaintoxinsthatareactiveonvoltage-sensitiveNa+channels,aswellasondelayedrectifierK+channelsbelongingtotheKv1family.ThisreportdescribesthepropertiesofanewsetofpeptidesfromAnemoniasulcatathatactasblockersofaspecificmemberoftheKv3potassiumchannelfamily.Thesetoxins,blooddepressingsubstance(BDS)-IandBDS-II,are43aminoacidslonganddifferatonlytwopositions.TheysharenosequencehomologieswithotherK+channeltoxinsfromseaanemones,suchasAsKS,AsKC,ShK,orBgK.InCOS-transfectedcells,theKv3.4currentwasinhibitedinareversiblemannerbyBDS-I,withanIC50valueof47nM.ThisinhibitionisspecificbecauseBDS-IfailedtoblockotherK+channelsintheKv1,Kv2,Kv3,andKv4subfamilies.InwardrectifierK+channelsarealsoinsensitivetoBDS-I.BDS-IandBDS-IIsharethesamebindingsiteonbrainsynapticmembranes,withK0.5valuesof12and19nM,respectively.WeobservedthatBDS-IandBDS-IIhavesomesequencehomologieswithotherseaanemoneNa+channelstoxins,suchasAsI,AsII,andAxI.However,theyhadaweakeffectontetrodotoxin-sensitiveNa+channelsinneuroblastomacellsandnoeffectonNa+channelsincardiacandskeletalmusclecells.BDS-IandBDS-IIarethefirstspecificblockersidentifiedsofarfortherapidlyinactivatingKv3.4channel.
Diochotetal(1998)SeaanemonepeptideswithaspecificblockingactivityagainstthefastinactivatingpotassiumchannelKv3.4.J.Biol.Chem.PMID:9506974.
Up-regulationandincreasedactivityofKV3.4channelsandtheiraccessorysubunitMinK-relatedpeptide2inducedbyamyloidpeptideareinvolvedinapoptoticneuronaldeath
TheaimofthepresentstudywastoinvestigatewhetherK(V)3.4channelsubunitsareinvolvedinneuronaldeathinducedbyneurotoxicbeta-amyloidpeptides(Abeta).Inparticular,totestthishypothesis,threemainquestionswereaddressed:1)whethertheAbetapeptidecanup-regulateboththetranscription/translationandactivityofK(V)3.4channelsubunitanditsaccessorysubunit,MinK-relatedpeptide2(MIRP2);2)whethertheincreaseinK(V)3.4expressionandactivitycanbemediatedbythenuclearfactor-kappaB(NF-kappaB)familyoftranscriptionalfactors;and3)whetherthespecificinhibitionofK(V)3.4channelsubunitrevertstheAbetapeptide-inducedneurodegenerationinhippocampalneuronsandnervegrowthfactor(NGF)-differentiatedPC-12cells.WefoundthatAbeta(1-42)treatmentinducedanincreaseinK(V)3.4andMIRP2transcriptsandproteins,detectedbyreversetranscription-polymerasechainreactionandWesternblotanalysis,respectively,inNGF-differentiatedPC-12cellsandhippocampalneurons.Patch-clampexperimentsperformedinwhole-cellconfigurationrevealedthattheAbetapeptidecausedanincreaseinI(A)currentamplitudecarriedbyK(V)3.4channelsubunits,asrevealedbytheirspecificblockadewithblooddepressingsubstance-I(BDS-I)inbothhippocampalneuronsandNGF-differentiatedPC-12cells.TheinhibitionofNF-kappaBnucleartranslocationwiththecellmembrane-permeablepeptideSN-50preventedtheincreaseinK(V)3.4proteinandtranscriptexpression.Inaddition,theSN-50peptidewasabletoblockAbeta(1-42)-inducedincreaseinK(V)3.4K(+)currentsandtopreventcelldeathcausedbyAbeta(1-42)exposure.Finally,BDS-IproducedasimilarneuroprotectiveeffectbyinhibitingtheincreaseinK(V)3.4expression.Asawhole,ourdataindicatethatK(V)3.4channelscouldbeanoveltargetforAlzheimer’sdiseasepharmacologicaltherapy.
Pannaccioneetal(2007)Up-regulationandincreasedactivityofKV3.4channelsandtheiraccessorysubunitMinK-relatedpeptide2inducedbyamyloidpeptideareinvolvedinapoptoticneuronaldeath.Mol.Pharmacol.PMID:17495071.
Voltage-dependentpotassiumcurrentsduringfastspikesofratcerebellarPurkinjeneurons:inhibitionbyBDS-Itoxin.
MartinaM.,etal.(2007)Voltage-dependentpotassiumcurrentsduringfastspikesofratcerebellarPurkinjeneurons:inhibitionbyBDS-Itoxin.J.Neurophysiol.PMID:17065256
ModulationofKv3subfamilypotassiumcurrentsbytheseaanemonetoxinBDS:significanceforCNSandbiophysicalstudies.
Kv3potassiumchannels,withtheirultra-rapidgatingandhighactivationthreshold,areessentialforhigh-frequencyfiringinmanyCNSneurons.Significantly,theKv3.4subunithasbeenimplicatedinthemajorCNSdisordersParkinson’sandAlzheimer’sdiseases,anditisclaimedthatselectivelytargetingthissubunitwillhavetherapeuticutility.PreviousworksuggestedthatBDStoxins(“blooddepressingsubstance,”fromtheseaanemoneAnemoniasulcata)werespecificblockersforrapidlyinactivatingKv3.4channels,andconsequentlythesetoxinsareincreasinglyusedasdiagnosticagentsforKv3.4subunitsincentralneurons.However,preciselyhowselectivearethesetoxinsforthisimportantCNSprotein?WeshowthatBDSisnotselectiveforKv3.4butmarkedlyinhibitscurrentthroughKv3.1andKv3.2channels.Inhibitioncomesaboutnotby“poreblock”butbystrikingmodificationofKv3gatingkineticsandvoltagedependence.ActivationandinactivationkineticsareslowedbyBDS-IandBDS-II,andV(1/2)foractivationisshiftedtomorepositivevoltages.AlaninesubstitutionmutagenesisaroundtheS3bandS4segmentsofKv3.2revealsthatBDSactsviavoltage-sensingdomains,and,consistentwiththis,ONgatingcurrentsfromnonconductingKv3.2aremarkedlyinhibited.Thealteredkineticsandgatingproperties,combinedwithlackofsubunitselectivitywithKv3subunits,seriouslyaffectstheusefulnessofBDStoxinsinCNSstudies.FurThermore,ourresultsdonoteasilyfitwiththevoltagesensor“paddle”structureproposedrecentlyforKvchannels.OurdatawillbeinformativeforexperimentsdesignedtodissectouttherolesofKv3subunitsinCNSfunctionanddysfunction.
ShukYinM.Yeung,DawnThompson,ZhurenWang,DavidFedida,BrianRobertson.ModulationofKv3subfamilypotassiumcurrentsbytheseaanemonetoxinBDS:significanceforCNSandbiophysicalstudies.TheJournalofNeuroscience25,8735-8745(2005).
ModulationofneuronalsodiumchannelsbytheseaanemonepeptideBDS-I.
Blood-depressingsubstanceI(BDS-I),a43amino-acidpeptidefromseaanemonevenom,isusedasaspecificinhibitorofKv3-familypotassiumchannels.WefoundthatBDS-Iactswithevenhigherpotencytomodulatespecifictypesofvoltage-dependentsodiumchannels.Inratdorsalrootganglion(DRG)neurons,3μMBDS-Istronglyenhancedtetrodotoxin(TTX)-sensitivesodiumcurrentbutweaklyinhibitedTTX-resistantsodiumcurrent.Inratsuperiorcervicalganglion(SCG)neurons,whichexpressonlyTTX-sensitivesodiumcurrent,BDS-Ienhancedcurrentelicitedbysmalldepolarizationsandsloweddecayofcurrentsatallvoltages(EC(50)∼300nM).BDS-IactedwithexceptionallyhighpotencyandefficacyonclonedhumanNav1.7channels,slowinginactivationby6-fold,withanEC(50)ofapproximately3nM.BDS-IalsoslowedinactivationofsodiumcurrentsinN1E-115neuroblastomacells(mainlyfromNav1.3channels),withanEC(50)∼600nM.InhippocampalCA3pyramidalneurons(mouse)andcerebellarPurkinjeneurons(mouseandrat),BDS-Ihadonlysmalleffectsoncurrentdecay(slowinginactivationby20-50%),suggestingrelativelyweaksensitivityofNav1.1andNav1.6channels.ThebiggesteffectofBDS-IincentralneuronswastoenhanceresurgentcurrentinPurkinjeneurons,aneffectreflectedinenhancementofsodiumcurrentduringtherepolarizationphaseofPurkinjeneuronactionpotentials.Overall,theseresultsshowthatBDS-Iactstomodulatesodiumchannelgatinginamannersimilartopreviouslyknownneurotoxinreceptorsite3anemonetoxinsbutwithdifferentisoformsensitivity.Mostnotably,BDS-IactswithveryhighpotencyonhumanNav1.7channels.
PinLiu,SooyeonJo,BruceP.Bean.ModulationofneuronalsodiumchannelsbytheseaanemonepeptideBDS-I.JournalofNeurophysiology107,3155-3167(2012).
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