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).
Smartox Biotechnolgy的多肽毒素产品如下：
1. 作用于钠离子通道(Sodium channel)的毒素
Toxin name | Catalog # | Target |
Phrixotoxin-3 | 13PHX003 | Selective blocker of Nav1.2 |
µ-conotoxin GIIIB | CON020 | Selective blocker of Nav1.4 |
µ-conotoxin CnIIIC | CON021 | Selective blocker of Nav1.4 |
μ-conotoxin PIIIA | 08CON006 | Selective blocker of Nav1.4 |
Jingzhaotoxin-III | 12JZH003 | Selective blocker of Nav1.5 |
ProTx-II | 07PTX002 | Selective blocker of Nav1.7 |
ProTx-II Biotin | 12PTB002 | Selective blocker of Nav1.7 |
ProTx-I | 12PTX001 | Blocker of Nav1.8, Nav1.2, Nav1.5, Nav1.7 |
Huwentoxin-I | 07HWT001 | Blocker of TTX-S |
Huwentoxin-IV | 08HWT002 | Blocker of TTX-S |
Hainantoxin-III | 13HTX003 | Blocker of TTX-S |
Hainantoxin-IV | 12HTX001 | Blocker of TTX-S |
GsAF-I | 12GSF001 | Blocker of TTX-S |
GsAF-II | 12GSF002 | Blocker of TTX-S |
2. 作用于钾离子通道(Potassium channel)的毒素
Toxin name | Catalog # | Target |
KCa channels | ||
Apamin 蜜蜂神经毒素 | 08APA001 | SK1, SK2, SK3 |
Charybdotoxin 蝎毒素 | 11CHA001 | KCa1.1, KCa3.1 - Kv1.2, Kv1.3, Kv1.6 |
Iberiotoxin | 12IBX001 | KCa1.1 |
Leiurotoxin 1 (Scyllatoxin) | 10LEI001 | SK1, SK2, SK3 |
Tamapin | 10TAM001 | SK1, SK2, SK3 |
Kaliotoxin-1 | 08KTX002 | BK, Kv1.1, Kv1.2, Kv1.3 |
Kv channels | ||
ShK | 08SHK001 | Kv1.3, Kv1.1, Kv1.4, Kv1.6 |
TMR-ShK | SAT001 | Kv1.3, Kv1.1 |
Margatoxin | 08MAG001 | Kv1.3 |
(Dap22)-ShK | 13SHD001 | Kv1.3 |
ADWX-1 | 13ADW001 | Kv1.3 |
HsTx1 | 08NEU001 | Kv1.3, Kv1.2 |
Agitoxin-2 | 13AGI002 | Kv1.3, Kv1.1 |
Maurotoxin | 08MAR001 | Kv1.2, KCa3.1 |
Guangxitoxin 1E | 11GUA002 | Kv2.1, Kv2.2 |
Stromatoxin 1 NEW | SCT01 | Kv2.1, Kv2.2 |
Kaliotoxin-1 | 08KTX002 | BK, Kv1.1, Kv1.2, Kv1.3 |
Charybdotoxin | 11CHA001 | KCa1.1, KCa3.1 - Kv1.2, Kv1.3, Kv1.6 |
Phrixotoxin-2 | PHX002 | Kv4.2, Kv4.3 |
AmmTx3 NEW | AMX001 | A-type potassium channels |
Inwardly rectifying potassium channels | ||
TertiapinQ | 08TER001 | Kir1.1, Kir3.1/3.4, Kir3.1/3.2-KCa1.1 |
hERG/Kv11.1 | ||
BeKm-1 | 13BEK001 | ERG1 |
3. 作用于钙离子通道(Calcium channel)的毒素
Toxin name | Catalog # | Target |
High voltage-gated Ca2+ channels | ||
ω-agatoxin IVA | 11AGA001 | P/Qtype |
ω-Conotoxin MVIIC | 08CON002 | P/Qtype, N-type |
ω-Conotoxin MVIIA | 08CON001 | N-type |
ω-Conotoxin GVIA | 08CON003 | N-type |
ω-Conotoxin SO3 | 08CON013 | N-type |
Huwentoxin I | 07HWT001 | N-type |
ProTx-II | 07PTX002 | T-type, L-type |
Intermediate voltage-gated Ca2+ channels | ||
SNX482 | 08SNX002 | R-type |
Low voltage-gated Ca2+ channels | ||
ProTx-I | 12PTX001 | T-type |
ProTx-II | 07PTX002 | T-type, L-type |
Ryanodine receptors | ||
Maurocalcine | 07PAU001 | Ryr1 |
4. 作用于氯离子通道(Chloride channel)的毒素
Toxin name | Catalog # | Target |
Chlorotoxin | 08CHL001 | Blocker of small conductance Cl- channels |
GaTx1 | 13GTX001 | Selective blocker of CFTR channel |
GaTx2 | 10GTX002 | Selective blocker of ClC-2 channel |
5. 作用于乙酰胆碱受体(Acetylcholine receptor)的毒素
Toxin name | Catalog # | Target |
α-conotoxin PeIA | 13CON017 | α9α10, α3β2 subunits |
α-Conotoxin PrXA | 13CON016 | α1/β1/ε/δ, α1/β1/γ/δ subunits |
Waglerin-1 | 12WAG001 | MusclenAChR |
α-conotoxin MI | 08CON012 | α1/δsubunits |
α-conotoxin GI | 08CON005 | α/δsite |
α-conotoxin IMI | 08CON011 | α7 homomeric nAChR |
α-conotoxin GID | CON019 | Blocker of α3β2, α7 and α4β2 nAChRs |
6. 含N-甲基-D-天冬氨酸NR2B
(NMDA, NR2B containing N-methyl-D-aspartate)
Conantokin-G
选择性、特异性抑制含NR2B的NMDAR。Conantokin-G能剂量依赖性抑制Ca2+内流，抑制NMDA诱导的兴奋性中毒效应。研究表明，在小鼠皮层神经元，Conantokin-G阻滞NMDA引发的电流信号的IC50值为480 nM。
7. 作用于酸敏感离子通道(ASIC channel, Acid-Sensing Ion Channel)的毒素
Toxin name | Catalog # | Target |
APETx2 | 07APE002 | Selective blocker of ASIC3 |
Psalmotoxin1/PcTx1 | 13PCT001 | Selective blocker of ASIC1a |
Ugr9-1 | 13UGR001 | Blocker of ASIC3 |
8. 作用于瞬时受体电位(TRP channel, transient receptor potential)的毒素
Toxin name | Catalog # | Target |
GsMTx4 | 08GSM001 | TRPC, TRPA |
Vanillotoxin3 | 10VAN003 | Activator of TRPV1 |
ProTx-I | 12PTX001 | Antagonist of TRPA1 |
9. 作用于嘌呤能通道(Purinergic channel)的毒素
Purotoxin-1
选择性抑制P2X3受体。100 nM Purotoxin-1 (PT-1)选择性抑制P2X3受体通道，在大鼠DRG神经元上，使用膜片钳实验表明：PT-1对电压门控通道和TRPV1均无抑制效应。10 µM ATP和100 µM α,β Methylene-ATP浓度下Purotoxin-1对P2X3受体有选择性作用，在该ATP浓度下Purotoxin-1对P2X2和杂化二聚体P2X2/3并无激动作用。Purotoxin-1对疼痛的潜在治疗作用。
10. 作用于其它膜受体通道(Others)的毒素
Smartox Biotechnology还提供其他类型的膜受体抑制剂：
Toxin name | Catalog # | Target |
Morphiceptin | 011CAS001 | Agonist of µ-opoid receptors |
Lys-conopressin G | 11CON14 | Vasopressin-like peptide |
GsMTx4 | 08GSM001 | Mechano sensitive ion channels |
Obtustatin | 10OBT001 | Blocks the binding of α1β1 integrin to collagen IV |
Rho-Conotoxin TIA | CON022 | Blocks α1-adrenergic receptor |
公司简介
Smartox Biotechnology是全球唯一一家专门生产动物毒液多肽毒素，用于细胞离子通道功能研究的生物医药公司。多肽毒素在生物制药领域具有重要的使用价值。
Smartox Biotechnology于2009年由来自Grenoble神经科学研究所(Grenoble Institute of Neuroscience)的Michel De Waard博士创立。Smartox Biotechnology专门研究动物毒液，制作合成多种毒液中的多肽成分（常称为毒素）。De Waard博士研究离子通道与毒素多肽的关系，尤其是鉴定、开发毒素多肽作为治疗性分子或细胞穿透肽(cell penetrating peptides, CPP)。其研究团队在毒液分离，药理性活性肽鉴定、富半胱氨酸肽定性、制作和优化等方面具有独特、丰富的经验。2010年，Smartox Biotechnolgy被法国研究部(Ministry of Research)授予“新兴企业OSEO奖(OSEO prize for emerging businesses)”。
总之，Smartox Biotechnolgy提供一系列高质量、具开创价值的多肽毒素。这些化合物在离子通道 研究中具有高的亲和性和选择性，是相应领域科学研究理想的生物毒素提供商和贴心的合作伙伴。
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