AmmTx3hasbeenoriginallyisolatedfromthevenomofthescorpionAndroctonusmauretanicusandisnowofferedbySmartoxinitssyntheticversion.AmmTx3bindsonitstargetA-typepotassiumchannelwithanaffinityof66pMinratbrainsynaptosomes(Kv4channels).Assuch,AmmTx3shouldrepresentanexcellenttooltostudyactionpotentialfiringfrequency,spikeinitiationandwaveforminexcitablecells.AmmTx3wasindeedfoundtoblockA-typepotassiumcurrentsfromcerebellumgranularcellsandfromstriatumneuronsbutwithIC50valuesof130nM.AmmTx3appearstobeaporeblockerofKv4.2andKv4.3andseemstorequiretheexpressionoftheKv4associatedproteinDPP6.Itshouldalsocontributetoourunderstandingoflearning,memoryandbehavior.AmmTx3sharesveryhighsequencehomologywithtwootherA-typepotassiumchannelblockers,Aa1fromAndroctonusaustralis(94%)andBmTx3fromButhusmartensi(91%),andaccordingtobindingexperimentsthesamechanneltargetaswell.AmmTx3isamemberofthea-KTX15familyoftoxinsandconsistofasinglechainof37aminoacidresidues,withanN-terminalpyroglutamate,cross-linkedbythreedisulfidebridges.
NewproductcitationDescription:
AAsequence:Pyr-Ile-Glu-Thr-Asn-Lys-Lys-Cys8-Gln-Gly-Gly-Ser-Cys13-Ala-Ser-Val-Cys17-Arg-Lys-Val-Ile-Gly-Val-Ala-Ala-Gly-Lys-Cys28-Ile-Asn-Gly-Arg-Cys33-Val-Cys35-Tyr-Pro-OH
Disulfidebonds:Cys8-Cys28,Cys13-Cys33andCys17-Cys35
Length(aa):37
Formula:C158H263N51O47S6
MolecularWeight:3821.52 Da
Appearance:whitelyophilizedsolid
Solubility:waterorsalinebuffer
CASnumber:
Source:Synthetic
Purityrate:>98%
Reference:
Dipeptidyl-peptidase-like-proteinsconferhighsensitivitytothescorpiontoxinAmmTX3toKv4-mediatedA-typeK+channels
K+channelscontainingKv4.2andKv4.3pore-formingsubunitsmediatemostofthesubthreshold-operatingsomatodendriticA-typeK+currentinCNSneurons.Thesechannelsarebelievedtobeimportantinregulatingthefrequencyofrepetitivefiring,thebackpropagationofactionpotentialintodendrites,anddendriticintegrationandplasticity.Moreover,theyhavebeenimplicatedinseveraldiseasesfrompaintoepilepsyandautismspectrumdisorders.Thelackoftoxinsthatspecificallyandefficientlyblockthesechannelshashamperedstudiesaimedatconfirmingtheirfunctionalroleandtheirinvolvementindisease.AmmTX3andotherrelatedmembersoftheα-KTX15familyofscorpiontoxinshavebeenshowntoblocktheA-typeK+currentinculturedneurons,buttheirspecificityhasbeenquestionedbecausethetoxinsdonotefficientlyblockthecurrentsmediatedbyKv4.2orKv4.3subunitsexpressedinheterologouscells.Hereweshowthatthehigh-affinityblockadeofKv4.2andKv4.3channelsbyAmmTX3dependsonthepresenceoftheauxiliarysubunitsDPP6andDPP10.TheseproteinsarethoughttobecomponentsoftheKv4channelcomplexinneuronsandtobeimportantforchannelexpressionindendrites.ThesestudiesvalidatetheuseofAmmTX3asablockeroftheKv4-mediatedA-typeK+currentinneurons.
MaffieJK.,etal.(2013)Dipeptidyl-peptidase-like-proteinsconferhighsensitivitytothescorpiontoxinAmmTX3toKv4-mediatedA-typeK+channels.JPhysiol.PMID:23440961
Scorpiontoxinsthatblocktransientcurrents(IA)ofratcerebellumgranularcells
Thiscommunicationisarevisionofthestate-of-the-artknowledgeofthefieldofscorpiontoxinsspecificfortheK(+)-channels,responsIBLefortheI(A)currentsofgranularcellsofratcerebellum,maintainedinvitroculture.Thereare6membersofthesub-familyalpha-KTx15knowntoaffecttheI(A)currents.Theyare:toxinsAa1fromAndroctonusaustralisGarzoni,BmTx3fromButhusmartensiKarch,AmmTx3fromAndroctonusmauretanicusmauretanicus,AATx1andAaTx2fromA.australisGarzoniandDiscrepinfromTityusdiscrepans.Theysharehighsequencesimilarity,apartfromDiscrepin,whichcausesanirreversibleeffectontheI(A)currentsandisthemostthoroughlystudiedtoxinofthesub-familyalpha-KTx15.Thethree-dimensionalstructureofDiscrepinwasdeterminedandaseriesofmutantsweresynthesizedandassayedinthesystemwiththeaimofidentifyingpossibleaminoacidsorsequencesegmentsresponsiblefortheirreversibleeffectfound.Inthisrevisionsomeunpublishedoriginaldataarealsoincludedtofosterfutureworkonthefield,aswellasashortdiscussiononsomerelevantaspectsstillpendingandpossiblelimitationsassociatedwiththestrategyproposed.
PrestipinoG.,etal.(2009)Scorpiontoxinsthatblocktransientcurrents(IA)ofratcerebellumgranularcells.ToxicolLett.PMID:19429236
Definitionofthealpha-KTx15subfamily
Threenovelscorpiontoxins,Aa1fromAndroctonusaustralis,BmTX3fromButhusmartensiandAmmTX3fromAndroctonusmauretanicuswereshownabletoselectivelyblockA-typeK+currentsincerebellumgranularcellsorculturedstriatumneuronsfromratbrain.Inelectrophysiologyexperiments,thetransientA-currentcompletelydisappearedwhen1microMofthetoxinswasappliedtotheexternalsolutionwhereasthesustainedK+currentwasunaffected.Thethreetoxinssharedhighsequencehomologies(morethan94%)andconstitutedanew‘short-chain’scorpiontoxinsubfamily:alpha-KTx15.Monoiododerivativeof125I-sBmTX3specificallyboundtoratbrainsynaptosomes.Underequilibriumbindingconditions,maximumbindingwas14fmol/mgofproteinandthedissociationconstant(Kd)was0.21nM.ThisKdvaluewasconfirmedbykineticexperiments(kon=6.0x10(6)M(-1)s(-1)andkoff=6.0x10(-4)s(-1)).CompetitionswithAmmTX3andAa1with125I-sBmTX3boundtoitsreceptoronratbrainsynaptosomesshowedthattheyfullyinhibitedthe125I-sBmTX3binding(Kivaluesof20and44pM,respectively),demonstratingunambiguouslythatthethreemoleculessharedthesametargetinratbrain.ApaneloftoxinsdescribedasspecificligandsfordifferentK+,Na+andCa2+channelswerenotabletodisplace125I-sBmTX3fromitsbindingsite.Thus,125I-sBmTX3isanewligandforastillunidentifiedtargetinratbrain.InautorADIography,thedistributionof125I-sBmTX3bindingsitesintheadultratbrainindicatedahighdensityof125I-sBmTX3receptorsinthestriatum,hippocampus,superiorcolliculus,andcerebellum.
VacherH.,etal.(2004)Definitionofthealpha-KTx15subfamily.Toxicon.PMID:15208021
Expandingthescorpiontoxina-KTX15familywithAmmTX3fromAndroctonusmauretanicus
Anoveltoxin,AmmTX3(3823.5Da),wasisolatedfromthevenomofthescorpionAndroctonusmauretanicus.Itshowed94%sequencehomologywithAa1fromAndroctonusaustralisand91%withBmTX3fromButhusmartensiwhich,respectively,blockA-typeK+currentincerebellumgranularcellsandstriatumculturedneurons.BindinganddisplacementexperimentsusingratbrainsynaptosomesshowedthatAmmTX3andAa1competedeffectivelywith125I-labelledsBmTX3binding.Theyfullyinhibitedthe125I-labelledsBmTX3binding(Kivaluesof19.5pmand44.2pm,respectively),demonstratingunambiguouslythatthethreemoleculessharedthesametargetinratbrain.Thespecificbindingparametersof125I-labelledAmmTX3foritssiteweredeterminedatequilibrium(Kd=66pm,BMAx=22fmolpermgofprotein).Finally,patch-clampexperimentsonstriatalneuronsinculturedemonstratedthatAmmTX3wasabletoinhibittheA-typeK+current(Ki=131nm).
VacherH.,etal.(2002)Expandingthescorpiontoxina-KTX15familywithAmmTX3fromAndroctonusmauretanicus.Eur.J.Biochem.PMID:12473099
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