Psalmotoxin-1(PcTx1,Pi-theraphotoxin-Pc1a) hasbeenisolatedfromthevenomoftheSpiderPsalmopoeuscambridgei(Trinidadchevrontarantula). PcTx1 isknowntoblockpotently(IC50 =1nM)andselectivelythe H+-gatedsodiumchannelASIC1a (acid-sensitiveionchannel1a).TheblockageisrapidandreversIBLe. PcTx1 candistinguishbetweenthetwoASIC1splicevariantsASIC1aandASIC1b. PcTx1 losesitscapacitytoblockASIC1aassoonasthissubunitisassociatedwithanothermemberofthefamily(ASIC2aorASIC3).PcTx1demonstratesananalgesiceffectinacuteandneuropathicpainmodels.
Fig1:effectof30nMPcTx1#13PCT001onASIC1aexpressedinoocytes. Inhibitionisnearlycompleteatthisconcentration.
Description:
AAsequence: Glu-Asp-Cys3-Ile-Pro-Lys-Trp-Lys-Gly-Cys10-Val-Asn-Arg-His-Gly-Asp-Cys17-Cys18-Glu-Gly-Leu-Glu-Cys23-Trp-Lys-Arg-Arg-Arg-Ser-Phe-Glu-Val-Cys33-Val-Pro-Lys-Thr-Pro-Lys-Thr-OH
Disulfidebonds: Cys3-Cys18,Cys10-Cys23 andCys17-Cys33
Length(aa): 40
Formula: C200H312N62O57S6
MolecularWeight: 4690.82Da
Appearance:Whitelyophilizedsolid
Solubility: waterandsalinebuffer
CASnumber: notavailable
Source: Synthetic
Purityrate: >98%
Reference:
HeteromericAcid-SensingIonChannels(ASICs)ComposedofASIC2bandASIC1aDisplayNovelChannelPropertiesandContributetoAcidosis-InducedNeuronalDeath
Acid-sensingionchannel(ASIC)subunitsassociatetoformhomomericorheteromericproton-gatedionchannelsinneuronsthroughoutthenervoussystem.TheASIC1asubunitplaysanimportantroleinestablishingthekineticsofproton-gatedcurrentsintheCNS,andactivationofASIC1ahomomericchannelsinducesneuronaldeathafterlocalacidosisthataccompaniescerebralischemia.TheASIC2bsubunitisexpressedinthebraininapatternthatoverlapsASIC1a,yetthecontributionofASIC2bhasremainedelusive.WefindthatcoexpressionofASIC2bwithASIC1ainXenopusoocytesresultsinnovelproton-gatedcurrentswithpropertiesdistinctfromASIC1ahomomericchannels.Inparticular,ASIC2b/1aheteromericchannelsareinhibitedbythenonselectivepotassiumchannelblockerstetraethylammoniumandbarium.Inaddition,steady-statedesensitizationisinducedatmorebasicpHvalues,andBigDynorphinsensitivityisenhancedintheseuniqueheteromericchannels.Culturedhippocampalneuronsshowproton-gatedcurrentsconsistentwithASIC2bcontribution,andthesecurrentsarelackinginneuronsfrommicewithanACCN1(ASIC2)genedisruption.Finally,wefindthattheseASIC2b/1aheteromericchannelscontributetoacidosis-inducedneuronaldeath.Together,ourresultsshowthatASIC2bconfersuniquepropertiestoheteromericchannelsincentralneurons.FurThermore,thesedataindicatethatASIC2,likeASIC1,playsaroleinacidosis-inducedneuronaldeathandimplicatetheASIC2b/1asubtypeasanovelpharmacologicaltargettopreventneuronalinjuryafterstroke.
SherwoodTW.,etal.(2011)HeteromericAcid-SensingIonChannels(ASICs)ComposedofASIC2bandASIC1aDisplayNovelChannelPropertiesandContributetoAcidosis-InducedNeuronalDeath.TheJournalofNeuroscience. PMID: 21715637
Psalmotoxin-1dockingtohumanacid-sensingionchannel-1
Acid-sensingionchannel-1(ASIC-1)isaproton-gatedionchannelimplicatedinnociceptionandneuronaldeathduringischemia.RecentlythefirstcrystalstructureofachickenASICwasobtained.Expandinguponthiswork,homologymodelsofthehumanASICswereconstructedandevaluated.Energy-minimizedstructuresweretestedforvaliditybyinsilicodockingofthemodelstopsalmotoxin-1,whichpotentlyinhibitsASIC-1andnotothermembersofthefamily.ThedataareconsistentwithpriorrADIoligandbindingandfunctionalassayswhilealsoexplainingtheselectivityofPcTX-1forhomomerichASIC-1a.Bindingenergycalculationssuggestthatthetoxinandchannelcreateacomplexthatismorestablethanthechannelalone.Thebindingisdominatedbythecoulombiccontributions,whichaccountforwhythetoxin-channelinteractionisnotobservedatlowpH.Thecomputationaldatawereexperimentallyverifiedwithsinglechannelandwhole-cellelectrophysiologicalstudies.Thesevalidatedmodelsshouldallowfortherationaldesignofspecificandpotentpeptidomimeticcompoundsthatmaybeusefulforthetreatmentofpainorischemicstroke.
QadriYJ., etal. (2009)Psalmotoxin-1dockingtohumanacid-sensingionchannel-1. JBC. PMID: 19395383
AtarantulapeptideagainstpainviaASIC1achannelsandopioidmechanisms
Psalmotoxin1,apeptideextractedfromtheSouthAmericantarantulaPsalmopoeuscambridgei,hasverypotentanalgesicpropertiesagainstthermal,mechanical,chemical,inflammatoryandneuropathicpaininrodents.Itexertsitsactionbyblockingacid-sensingionchannel1a,andthisblockaderesultsinanactivationoftheendogenousenkephalinpathway.TheanalgesicpropertiesofthepeptidearesuppressedbyantagoNISTsofthemuanddelta-opioidreceptorsandarelostinPenk1-/-mice.
MazzucaM., etal. (2007)AtarantulapeptideagainstpainviaASIC1achannelsandopioidmechanisms. NatNeurosci.PMID: 17632507
CationselectivityandinhibitionofmalignantgliomaNa+channelsbyPsalmotoxin1
Psalmotoxin1(acomponentofthevenomofaWestIndiestarantula)isa40-aminoacidpeptidethatinhibitscationcurrentsmediatedbyacid-sensingionchannels(ASIC).InthisstudyweperformedelectrophysiologicalexperimentstotestthehypothesisthatPsalmotoxin1(PcTX1)inhibitsNa+currentsinhigh-gradehumanastrocytomacells(glioblastomamultiforme,orGBM).Inwholecellpatch-clampedculturedGBMcells,thepeptidetoxinquicklyandreversiblyinhibitedbothinwardandoutwardcurrentwithanIC50of36+/-2pM.ThesameinhibitionwasobservedinfreshlyresectedGBMcells.However,whenthesameexperimentwasperformedonnormalhumanastrocytes,thetoxinfailedtoinhibitthewholecellcurrent.WealsodeterminedacationicselectivitysequenceforinwardcurrentsinthreeculturedGBMcelllines(SK-MG-1,U87-MG,andU251-MG).TheselectivitysequenceyieldedauniquebiophysicalfingerprintwithinwardK+conductanceapproximatelyfourfoldgreaterthanthatofNa+,Li+,andCa2+.TheseobservationssuggestthatPcTX1mayproveusefulindeterminingwhetherGBMcellsexpressaspecificASIC-containingionchanneltypethatcanserveasatargetforbothdiagnosticandtherapeutictreatmentsofaggressivemalignantgliomas.
BubienJK., etal. (2004)CationselectivityandinhibitionofmalignantgliomaNa+channelsbyPsalmotoxin1. AmJPhysiolCellPhysiol. PMID: 15253892
RecombinantproductionandsolutionstructureofPcTx1,thespecificpeptideinhibitorofASIC1aproton-gatedcationchannels
Acid-sensingionchannels(ASICs)arethoughttobeimportantionchannels,particularlyfortheperceptionofpain.Someofthemmayalsocontributetosynapticplasticity,learning,andmemory.Psalmotoxin1(PcTx1),thefirstpotentandspecificblockeroftheASIC1aproton-sensingchannel,hasbeensuccessfullyexpressedintheDrosophilamelanogasterS2cellrecombinantexpressionsystemusedhereforthefirsttimetoproduceaspidertoxin.Therecombinanttoxinwasidenticalinallrespectstothenativepeptide,anditsthree-dimensionalstructureinsolutionwasdeterminedbymeansof(1)H2DNMRspectroscopy.SurfacecharacteristicsofPcTx1provideinsightsonkeystructuralelementsinvolvedinthebindingofPcTx1toASIC1achannels.Theyappeartobelocalizedinthebeta-sheetandthebeta-turnlinkingthestrands,asindicatedbyelectrostaticanisotropycalculations,surfacechargedistribution,andthepresenceofresiduesknowntobeimplicatedinchannelrecognitionbyotherinhibitorcystineknot(ICK)toxins.
Darbon,H., etal. (2003)RecombinantproductionandsolutionstructureofPcTx1,thespecificpeptideinhibitorofASIC1aproton-gatedcationchannels, ProteinSci. PMID: 12824480
Isolationofatarantulatoxinspecificforaclassofproton-gatedNa+channels
Acidsensingisassociatedwithnociception,tastetransduction,andperceptionofextracellularpHfluctuationsinthebrain.Acidsensingiscarriedoutbythesimplestclassofligand-gatedchannels,thefamilyofH(+)-gatedNa(+)channels.Thesechannelshaverecentlybeenclonedandbelongtotheacid-sensitiveionchannel(ASIC)family.Toxinsfromanimalvenomshavebeenessentialforstudiesofvoltage-sensitiveandligand-gatedionchannels.Thispaperdescribesanovel40-aminoacidtoxinfromtarantulavenom,whichpotentlyblocks(IC(50)=0.9nm)aparticularsubclassofASICchannelsthatarehighlyexpressedinbothcentralnervoussystemneuronsandsensoryneuronsfromdorsalrootganglia.ThischanneltypehaspropertiesidenticaltothosedescribedforthehomomultimericassemblyofASIC1a.HomomultimericassembliesofothermembersoftheASICfamilyandheteromultimericassembliesofASIC1awithotherASICsubunitsareinsensitivetothetoxin.Thenewtoxinisthefirsthighaffinityandhighlyselectivepharmacologicalagentforthisnovelclassofionicchannels.Itwillbeimportantforfuturestudiesoftheirphysiologicalandphysio-pathologicalroles.
Lazdunski,M., etal. (2000)Isolationofatarantulatoxinspecificforaclassofproton-gatedNa+channels, JBiolChem. PMID: 10829030
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