Guangxitoxin-1E(GxTx-1E) wasisolatedfromthevenomofChilobrachysjingzhao(Chineseearthtigertarantula).Guangxitoxin-1E wasshowntoblock Kv2.1/KCNB1,Kv2.2/KCNB2andKv4.3/KCND3channels withoutsignificanteffectonKv1.2/KCNA2,Kv1.3/KCNA3,Kv1.5/KCNA5,Kv3.2/KCNC2,Cav1.2/CACNA1C,Cav2.2/CACNA1B,Nav1.5/SCN5A,Nav1.7/SCN9AorNav1.8/SCN10Achannels. Guangxitoxin-1E inhibitsKv2.1withanIC50 valueof1nMandKv2.2withanIC50 valueof3nM.BlockofKv4.3occursat10-20foldhigherconcentrations.Guangxitoxin-1E actsasagatingmodifiersinceitshiftsthevoltage-dependenceofKv2.1K+ currentstowardsdepolarizedpotentials.Inpancreaticbeta-cells, Guangxitoxin-1E enhancesglucose-stimulatedinsulinsecretion bybroadeningthecellactionpotentialandenhancingcalciumoscillations.
RecentlyquotedDescription:
AAsequence: Glu-Gly-Glu-Cys4-Gly-Gly-Phe-Trp-Trp-Lys-Cys11-Gly-Ser-Gly-Lys-Pro-Ala-Cys18-Cys19-Pro-Lys-Tyr-Val-Cys24-Ser-Pro-Lys-Trp-Gly-Leu-Cys31-Asn-Phe-Pro-Met-Pro-OH
Presumeddisulfidebridgepattern:Cys4-Cys19,Cys11-Cys24,Cys18-Cys31
Length(aa): 36
Formula: C178H248N44O45S7
MolecularWeight: 3948.70Da
Appearance:Whitelyophilizedsolid
Solubility: waterorsalinebuffer
CASnumber: notavailable
Source: Synthetic
Purityrate: >95%
Reference:
Theroleofvoltage-gatedpotassiumchannelsKv2.1andKv2.2intheregulationofinsulinandsomatostatinreleasefrompancreaticislets
Thevoltage-gatedpotassiumchannelsKv2.1&Kv2.2arehighlyexpressedinpancreaticislets,yettheircontributiontoislethormonesecretionisnotfullyunderstood.HereweinvestigatetheroleofKv2channelsinpancreaticisletsusingacombinationofgenetic&pharmacologicapproaches.Pancreaticβ-cellsfromKv2.1(-/-)micepossessreducedKvcurrent&displaygreaterglucose-stimulatedinsulinsecretion(GSIS)relativetoWTβ-cells.InhibitionofKv2.xchannelswithselectivepeptidyl[guangxitoxin-1E(GxTX-1E)]orsmallmolecule(RY796)inhibitorsenhancesGSISinisolatedwild-type(WT)mouse&humanislets,butnotinisletsfromKv2.1(-/-)mice.However,inWTmiceneitherinhibitorimprovedglucosetoleranceinvivo.GxTX-1E&RY796enhancedsomatostatinreleaseinisolatedhuman&mouseislets&insituperfusedpancreatafromWT&Kv2.1(-/-)mice.Kv2.2silencinginmouseisletsbyadenovirus-smallhairpinRNA(shRNA)specificallyenhancedisletsomatostatin,butnotinsulin,secretion.Inmicelackingsomatostatinreceptor5,GxTX-1Estimulatedinsulinsecretion&improvedglucosetolerance.Collectively,thesedatashowthatKv2.1regulatesinsulinsecretioninβ-cells&Kv2.2modulatessomatostatinreleaseinδ-cells.DevelopmentofselectiveKv2.1inhibitorswithoutcrossinhibitionofKv2.2mayprovidenewavenuestopromoteGSISforthetreatmentoftype2diabetes.
LiXN., etal. (2013)Theroleofvoltage-gatedpotassiumchannelsKv2.1andKv2.2intheregulationofinsulinandsomatostatinreleasefrompancreaticislets. JPharmacolExpTher. PMID: 23161216
Regulationofvoltage-gatedK+channelsbyglucosemetabolisminpancreaticbeta-cells
Regulationofdelayedrectifier-typeK(+)channels(Kv-channels)byglucosewasstudiedinratpancreaticbeta-cells.TheKv-channelcurrentwasincreasedinamplitudesbyincreasingglucoseconcentrationfrom2.8to16.6mM,whileitwasdecreasedby2.8mMglucoseinareversIBLemanner(down-regulation)inbothperforated&conventionalwhole-cellmodes.ThecurrentwasdecreasedbyFCCP,intraPipette0mMATPorAMPPNP.Glyceraldehyde,pyruvicacid,2-ketoisocaproicacid,&10mMMgATPpreventedthedown-regulationinducedby2.8mMorlessglucose.TheresidualcurrentaftertreatmentwithKv2.1-specificblocker,guangxitoxin-1E,wasunchangedbyloweringorincreasingglucoseconcentration.WeconcludethatglucosemetabolismregulatesKv2.1channelsinratsbeta-cellsviaalteringMgATPlevels.
YoshidaM., etal. (2009)Regulationofvoltage-gatedK+channelsbyglucosemetabolisminpancreaticbeta-cells. FEBSLett. PMID: 19500583
AnautomatedelectrophysiologyserumshiftassayforK(V)channels
ThepresenceofseruminBIOLOGicalsamplesoftennegativelyimpactsthequalityofinvitroassays.However,assaystolerantofserumareusefulforassessingtheinvivoavailABIlityofasmallmoleculeforitstarget.Electrophysiologyassaysofionchannelsarenotoriouslysensitivetoserumbecauseoftheirrelianceontheinteractionoftheplasmamembranewitharecordingelectrode.Hereweinvestigatethetoleranceofanautomatedelectrophysiologyassayforavoltage-gatedpotassium(K(V))channeltoserum&purifiedplasmaproteins.Thedelayedrectifierchannel,K(V)2.1,stablyexpressedinChinesehamsterovarycellsproduceslarge,stablecurrentsontheIonWorksQuattroplatform(MDSAnalyticalTechnologies,Sunnyvale,CA),makingitanidealtestcase.K(V)2.1currentsrecordedonthisplatformarehighlyresistanttoserum,allowingrecordingsinashighas33%serum.UsingasetofcompoundsrelatedtotheK(V)channelblocker,4-phenyl-4-[3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl]cyclohexanone,weshowthatshiftsincompoundpotencywithwholeserumorisolatedserumproteinscanbereliablymeasuredwiththisassay.Importantly,thisassayisalsorelativelyinsensitivetoplasma,allowingthecreationofabioassayforinhibitorsofK(V)2.1channelactivity.Hereweshowthatsuchabioassaycanquantifythelevelsofthegatingmodifier,guangxitoxin-1E,inplasmasamplesfrommicedosedwiththepeptide.Thisstudydemonstratestheutilityofusinganautomatedelectrophysiologyplatformformeasuringserumshifts&forbioassaysofionchannelmodulators.
RatliffKS., etal.(2008)AnautomatedelectrophysiologyserumshiftassayforK(V)channels. AssayDrugDevTechnol.PMID: 18471078
Gatingmodifierpeptidesasprobesofpancreaticbeta-cellphysiology
Pancreaticbeta-cellsdepolarizeinresponsetoglucose&firecalcium-dependentactionspotentialsthattriggerinsulinsecretion.Themajorcurrentresponsibleforactionpotentialrepolarizationinthesecellsisadelayedrectifier&Kv2.1subunitsarethoughtbeamajorcontributorofthedelayedrectifierchannels.Hence,blockersofKv2.1channelsmightprolongactionpotentials&enhancecalciuminflux&insulinsecretion.However,thelackofspecificsmallmoleculeKv2.1inhibitorshashinderedthetestingofthismechanism.Importantly,severalgatingmodifierpeptidesinhibitKv2.1channelsinarelativelyspecificfashion.Hanatoxin(HaTX)&guangxitoxin-1(GxTX-1)areexamplesthathavebeenusedtoprobetheroleofKv2.1channelsinbeta-cellphysiology.BothHaTX&GxTX-1stronglyinhibittheKvcurrentofbeta-cellsfromvariousspecies,arguingthatKv2.1subunitscontributesignificantlytothebeta-celldelayedrectifier.GxTX-1prolongsglucose-triggeredactionpotentials,enhancesglucose-dependentintracellularcalciumelevations&augmentsglucose-dependentinsulinsecretion.Takentogether,thesedatasuggestthatblockersofKv2.1channelsmaybeausefulapproachtothedesignofnoveltherapeuticagentsforthetreatmentoftype2diabetes.Thesestudieshighlighttheutilityofgatingmodifierpeptidesinthestudyofphysiologicalsystems.
HerringtonJ.,(2009)Gatingmodifierpeptidesasprobesofpancreaticbeta-cellphysiology. Toxicon. PMID: 17101164
SNAP-25(1-180)enhancesinsulinsecretionbyblockingKv2.1channelsinratpancreaticisletbeta-cells
Voltage-gatedoutwardK(+)currentsfrompancreaticisletbeta-cellsareknowntorepolarizetheactionpotentialduringaglucosestimulus,&consequentlytomodulateCa(2+)entry&insulinsecretion.ThevoltagegatedK(+)(Kv)channel,Kv2.1,whichisexpressedinratisletbeta-cells,mediatesover60%oftheKvoutwardK(+)currents.AnovelpeptidylinhibitorofKv2.1/Kv2.2channels,guangxitoxin(GxTX)-1,hasbeenshowntoenhanceglucose-stimulatedinsulinsecretion.Here,weshowthatSNAP-25(1-180)(S180),anN-terminalSNAP-25domain,butnotSNAP-25(1-206)(S206),inhibitsKvcurrent&enhancesglucose-dependentinsulinsecretionfromratpancreaticisletbeta-cells,&furThermore,thisenhancementwasinducedbytheblockadeoftheKv2.1current.ThisstudyindicatesthattheKv2.1channelisapotentialtargetfornoveltherapeuticagentdesignforthetreatmentoftype2diabetes.Thistargetmaypossessadvantagesovercurrently-usedtherapies,whichmodulateinsulinsecretioninaglucose-independentmanner.
ZhuangGQ., etal. (2009)SNAP-25(1-180)enhancesinsulinsecretionbyblockingKv2.1channelsinratpancreaticisletbeta-cells. BiochemBiophysResCommun. PMID: 19103161
Blockersofthedelayed-rectifierpotassiumcurrentinpancreaticbeta-cellsenhanceglucose-dependentinsulinsecretion
Delayed-rectifierK+currents(I(DR))inpancreaticbeta-cellsarethoughttocontributetoactionpotentialrepolarization&therebymodulateinsulinsecretion.Thevoltage-gatedK+channel,K(V)2.1,isexpressedinbeta-cells,&thebiophysicalcharacteristicsofheterologouslyexpressedchannelsaresimilartothoseofI(DR)inrodentbeta-cells.AnovelpeptidylinhibitorofK(V)2.1/K(V)2.2channels,guangxitoxin(GxTX)-1(half-maximalconcentrationapproximately1nmol/l),hasbeenpurified,characterized,&usedtoprobethecontributionofthesechannelstobeta-cellphysiology.Inmousebeta-cells,GxTX-1inhibits90%ofI(DR)&,asforK(V)2.1,shiftsthevoltagedependenceofchannelactivationtomoredepolarizedpotentials,acharacteristicofgating-modifierpeptides.GxTX-1broadensthebeta-cellactionpotential,enhancesglucose-stimulatedintracellularcalciumoscillations,enhancesinsulinsecretionfrommousepancreaticisletsinaglucose-dependentmanner.Thesedatapointtoamechanismforspecificenhancementofglucose-dependentinsulinsecretionbyapplyingblockersofthebeta-cellI(DR),whichmayprovideadvantagesovercurrentlyusedtherapiesforthetreatmentoftype2diabetes.
HerringtonJ., etal.(2006)Blockersofthedelayed-rectifierpotassiumcurrentinpancreaticbeta-cellsenhanceglucose-dependentinsulinsecretion. Diabetes. PMID: 16567526
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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