Tertiapin hasbeenisolatedfromthevenomoftheHoneybee Apismellifera. Tertiapin-Q isanoxidation-resistantmutantofthewild-typetertiapinwhereMethionine13hasbeenreplacedbyaGlutamine. Tertiapin-Q blockstheinwardlyrectifying Kir1.1(ROMK1) and Kir3.1/3.4(GIRK1/GIRK4alsoknownasIKACh) potassiumchannelswithKdvaluesofaround2nMand8nMrespectively.Tertiapin-Q alsoinhibitscalcium-activatedlargeconductance BKpotassiumchannels (KCa1.1)inaconcentrationandvoltage-dependentmanner(IC50 ~5nM),inadditiontoinhibiting Kir3.1/3.2(GIRK1/GIRK2) heteromultimerpotassiumchannelswithaKdcloseto270nM. Tertiapin-Q canpreventdose-dependentacetylcholine(ACh)-inducedatrioventricularblocksinmammalianhearts,asKCNJ3/KCNJ5channels(alsonamedI(KACh)),areactivatedbyAChfoundinmammalianmyocytes.
Description:
AAsequence: Ala-Leu-Cys3-Asn-Cys5-Asn-Arg-Ile-Ile-Ile-Pro-His-Gln-Cys14-Trp-Lys-Lys-Cys18-Gly-Lys-Lys-NH2
Disulfidebonds: Cys3-Cys14 andCys5-Cys18
Length(aa): 21
Formula: C106H175N35O24S4
MolecularWeight: 2452Da
Appearance:Whitelyophilizedsolid
Solubility: waterandsalinebuffer
CASnumber: [252198-49-5]Source: Synthetic
Purityrate: >97%
Reference:
CharacterizationofKir1.1channelswiththeuseofarADIolabeledderivativeoftertiapin,Biochemistry
Inwardrectifierpotassium channels (Kir)playcriticalrolesincellphysiology.Despiterepresentingthesimplesttetramericpotassiumchannelstructures,thepharmacologyofthischannelfamilyremainslargelyundeveloped.Inthisrespect, tertiapin (TPN),a21aminoacidpeptideisolatedfrombeevenom,hasbeenreportedtoinhibit Kir1.1 andKir3.1/3.4 channels withhighaffinitybybindingtotheM1-M2linkerregionofthese channels.Thefeaturesofthepeptide-channelinteractionhavebeenexploredelectrophysiologically,&thesestudieshaveidentifiedwaysbywhichtoalterthecompositionofthepeptidewithoutaffectingitsBIOLOGicalactivity.Inthepresentstudy,theTPN derivative,TPN-Y1/K12/Q13,hasbeensynthesized&radiolabeled tohighspecificactivitywith(125)I.TPN-Y1/K12/Q13&mono-iodo-TPN-Y1/K12/Q13([(127)I]TPN-Y1/K12/Q13)inhibitwithhighaffinityratbutnothuman Kir1.1 channels stablyexpressedinHEK293cells.[(125)I]TPN-Y1/K12/Q13bindsinasaturable,time-dependent,&reversIBLemannertoHEK293cellsexpressingrat Kir1.1,aswellastomembranesderivedfromthesecells,&thepharmacologyofthebindingreactionisconsistentwithpeptidebindingto Kir1.1 channels.Studiesusingchimeric channels indicatethatthedifferencesinTPNsensitivitybetweenrat&human Kir1.1 channels areduetothepresenceoftwononconservedresidueswithintheM1-M2linkerregion.Whentheseresultsaretakentogether,theydemonstratethat[(125)I]TPN-Y1/K12/Q13representsthefirsthighspecificactivityradioligandforstudyingrat Kir1.1 channels&suggestitsutilityforidentifyingotherKirchannelmodulators.
Felix,J.P.,etal.(2006)CharacterizationofKir1.1channelswiththeuseofaradiolabeledderivativeoftertiapin,Biochemistry. PMID: 16906771
Tertiapin-QblocksrecombinantandnativelargeconductanceK+channelsinause-dependentmanner
Tertiapin,ashortpeptidefromhoneybeevenom,hasbeenreportedtospecificallyblocktheinwardlyrectifying K(+)(Kir) channels,includingGprotein-coupledinwardlyrectifyingpotassiumchannel(GIRK)1+GIRK4heteromultimers&ROMK1homomultimers.Inthepresentstudy,theeffectsofastable&functionallysimilarderivativeoftertiapin, tertiapin-Q,wereexaminedon recombinant humanvoltage-dependentCa(2+)-activated largeconductance K(+)channel(BKorMaxiK;alpha-subunitorhSlo1homomultimers)&mouseinwardlyrectifyingGIRK1+GIRK2(i.e.,Kir3.1&Kir3.2)heteromultimeric K(+) channels expressedinXenopusoocytes&inculturednewbornmousedorsalrootganglion(DRG)neurons.Intwo-electrodevoltage-clampedoocytes, tertiapin-Q (1-100nM)inhibitedBK-type K(+) channels inause-&concentration-dependent manner.Wealsoconfirmedtheinhibitionof recombinant GIRK1+GIRK2heteromultimersby tertiapin-Q,whichhadnoeffectonendogenousdepolarization-&hyperpolarization-activatedcurrentssensitivetoextracellulardivalentcations(Ca(2+),Mg(2+),Zn(2+),&Ba(2+))indefolliculatedoocytes.Involtage-clampedDRGneurons, tertiapin-Q voltage-&use-dependentlyinhibitedoutwardlyrectifying K(+)currents,butCs(+)-blockedhyperpolarization-activatedinwardcurrentsincludingI(H)wereinsensitiveto tertiapin-Q,baclofen,barium,&zinc,suggestingabsenceoffunctionalGIRK channels inthenewborn.Undercurrent-clampconditions, tertiapin-Q blockedtheactionpotentialafterhyperpolarization(AHP)&increasedactionpotentialdurationinDRGneurons.Takentogether,theseresultsdemonstratethattheblockingactionsof tertiapin-Q arenotspecifictoKir channels&thattheblockadeofrecombinant BK channels&native neuronalAHPcurrentsis use-dependent.InhibitionofspecifictypesofKir&voltage-dependentCa(2+)-activated K(+) channels by tertiapin-Q atnanomolarrangeviadifferentmechanismsmayhaveimplicationsinpainphysiology&therapy.
Kanjhan,R.,C etal.(2005)Tertiapin-QblocksrecombinantandnativelargeconductanceK+channelsinause-dependentmanner, JPharmacolExpTher. PMID: 15947038
Titrationoftertiapin-QinhibitionofROMK1channelsbyextracellularprotons
Tertiapin-Q (TPN(Q)),ahoneybeetoxinderivative,inhibitsinward-rectifierK(+) channels bybindingtotheirexternalvestibule.InthepresentstudywefoundthatTPN(Q) inhibition ofthe channels isprofoundlyaffectedby extracellular pH.ThispHdependencemainlyreflects titration ofhistidineresidue12inTPN(Q)by extracellular protons,sinceitlargelyvanisheswhenthehistidineresidueisreplacedwithalanine.Notsurprisingly,thisalaninederivativeofTPN(Q)bindstothechannelwithmuchloweraffinity.QuantitativeThermodynamiccycleanalysisshowsthatdeprotonationofthehistidineresiduereducestheTPN(Q)-ROMK1 bindingenergyby1.6kcal/mol.ToeliminatepHsensitivitybutretainhighaffinity,wederivatizedTPN(Q)byreplacinghistidine12withlysine.Thisderivative-denotedtertiapin-KQ(TPN(KQ))-notonlyispracticallyinsensitiveto extracellular pHbutalsobindstothechannelwithevenhigheraffinitythanTPN(Q)at extracellular pH7.6.
Ramu,Y., etal.(2001)Titrationoftertiapin-QinhibitionofROMK1channelsbyextracellularprotons, Biochemistry. PMID: 11297426
TertiapinpotentlyandselectivelyblocksmuscarinicK(+)channelsinrabbitcardiacmyocytes
Tertiapin isa21-residuepeptideisolatedfromhoneybeevenoms.Arecentstudyindicatedthat tertiapin isapotentblockerofcertaintypesofinwardlyrectifying K(+)(Kir) channels ().Weexaminedtheeffectof tertiapin onionchannelcurrentsin rabbit cardiac myocytes usingthepatch-clamptechnique.Inthewhole-cellconfiguration, tertiapin fullyinhibitedacetylcholine(1microM)-induced muscarinic K(+)(K(ACh))channelcurrentsinatrialmyocytes withthehalf-maximuminhibitoryconcentrationofapproximately8nMthroughapproximately1:1stoichiometry.Thepotencyof tertiapin ininhibiting K(ACh) channels wasnotsignificantlydifferentat-40&-100mV. Tertiapin alsoinhibitedthe K(ACh)channelpreactivatedbyintracellularguanosine5′-O-(3-thiotriphosphate),anonhydrolyzableGTPanalog.AconstitutivelyactiveKirchannel,theI(K1)channel,wasatleast100timeslesssensitiveto tertiapin.AnotherKirchannelin cardiac myocytes,theATP-sensitive K(+)channel,wasvirtuallyinsensitiveto tertiapin (1microM).Thevoltage-dependent K(+)&theL-typeCa(2+) channels werenotaffectedby tertiapin (1microM).Atthesingle-channellevel, tertiapin inhibitedtheK(ACh)channelfromtheoutsideofthemembranebyreducingtheNP(o)(Nisthenumberoffunctional channels,&theP(o)istheopenprobABIlityofeachchannel)withoutaffectingthesingle-channelconductanceorfastkinetics.Therefore, tertiapin potently&selectively blocks the K(ACh)channelin cardiac myocytes inareceptor-&voltage-independentmanner. Tertiapin isanovelpharmacologicaltooltoidentifythefunctionalroleofthe K(ACh)channelintheparasympatheticregulationoftheheartbeat.
Kitamura,H., etal.(2000)TertiapinpotentlyandselectivelyblocksmuscarinicK(+)channelsinrabbitcardiacmyocytes, JPharmacolExpTher. PMID: 10734170
Mechanismsofinward-rectifierK+channelinhibitionbytertiapin-Q,Biochemistry
Tertiapin-Q(TPN(Q))isaderivativeofhoneybeetoxintertiapin(TPN)whosemethionineresidueisreplacedwithaglutamineresidue.TPN(Q)inhibitstheROMK1&GIRK1/4inward-rectifierK(+)channelswithaffinitiesverysimilartoTPN.However,unlikenativeTPN,TPN(Q)isnonoxidizablebyair.ThestabilityofTPN(Q)allowsustoinvestigatehowitinteractswiththetargetedchannels.WefoundthattheinteractionbetweenTPN(Q)&theROMK1channelisabimolecularreaction,i.e.,oneTPN(Q)moleculebindstoonechannel.TheinteractionsurfaceinTPN(Q)isprimarilyformedbyitsalphahelixratherthanthebetasheetswithwhichscorpiontoxinsformtheirinteractionsurface.Themutagenesisstudiesonboththechannel&TPN(Q)togetherstronglysuggestthattoblocktheK(+)poreTPN(Q)plugsitsalphahelixintothevestibuleoftheK(+)pore,whileleavingtheextendedstructuralportionstickingoutofthevestibuleintotheextracellularmedia.
Jin,W., etal.(1999)Mechanismsofinward-rectifierK+channelinhibitionbytertiapin-Q, Biochemistry. PMID: 10572004
Synthesisofastableformoftertiapin:ahigh-affinityinhibitorforinward-rectifierK+channels
Tertiapin (TPN),asmallproteinderivedfromhoneybeevenom,inhibitstheGIRK1/4&ROMK1 channels withnanomolaraffinities.Methionineresidue13inTPNinteractswithresidueF148inthechannel,locatedjustoutsideofthenarrowregionoftheROMK1pore.ThemethionineresidueinTPNcanbeoxidizedbyair,whichsignificantlyhindersTPNbindingtothe channels.ToovercomethereductioninTPNaffinityduetooxidationofM13,wereplacedM13inTPNwithfourteendifferentresidues.Outofthefourteenderivatives,onlytheoneinwhichM13wasreplacedbyglutamine,TPNQ,bindstothechannelwithaKivalueverysimilartothatofnativeTPN.SinceTPNQis stable&functionallyresemblesnativeTPN,itwillbeaveryusefulmolecularprobeforstudyingthe inward-rectifier K+ channels.
Jin,W.,andLu,Z.(1999)Synthesisofastableformoftertiapin:ahigh-affinityinhibitorforinward-rectifierK+channels, Biochemistry. PMID: 10572003
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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