Rho-conotoxinTIAisaconopeptidethathasbeenisolatedfromthevenomofthefish-huntingmarineconesnail Conustulipa. Rho-conotoxinTIA isaselectiveantagoNISTof α1-adrenoreceptor (α1A-,α1B–andα1D-AR).Itactsnon-competitivelyontoα1B-adrenoreceptor butcompetitivelyon α1A-adrenoreceptor and α1D-adrenoreceptor.ThemostimportantresidueforactivityisArg4. Rho-conotoxinTIA is10-foldselectiveforhuman α1B-adrenoreceptor over α1A-adrenoreceptorand α1D-adrenoreceptor.TheIC50 valuesfor Rho-conotoxinTIA forinhibitionof 125I-BEwere18nMforhumanα1A-AR,2nMforα1B-ARand25nMforα1D-AR.
Description:
AAsequence:Phe-Asn-Trp-Arg-Cys5-Cys6-Leu-Ile-Pro-Ala-Cys11-Arg-Arg-Asn-His-Lys-Lys-Phe-Cys19-NH2
Disulfidebonds:Cys5-Cys11 andCys6-Cys19
Length(aa):19
Formula:C105H160N36O21S4
MolecularWeight:2390.90 Da
Appearance:Whitelyophilizedsolid
Solubility:aqueousbuffer
CASnumber:notavailable
Source:Synthetic
Purityrate:>95%
Reference:
Allostericalpha1-AdrenoreceptorAntagonismbytheConopeptiderho-TIA
ApeptidecontainedinthevenomofthepredatorymarinesnailConustulipa,rho-TIA,haspreviouslybeenshowntopossessalpha1-adrenoreceptorantagonistactivity.Here,wefurthercharacterizeitspharmacologicalactivityaswellasitsstructure-activityrelationships.Intheisolatedratvasdeferens,rho-TIAinhibitedalpha1-adrenoreceptor-mediatedincreasesincytosolicCa2+concentrationthatweretriggeredbynorepinephrine,butdidnotaffectpresynapticalpha2-adrenoreceptor-mediatedresponses.InrADIoligandbindingassaysusing[125I]HEAT,rho-TIAdisplayedslightlygreaterpotencyatthealpha1Bthanatthealpha1Aoralpha1Dsubtypes.Moreover,althoughitdidnotaffecttherateofassociationfor[3H]prazosinbindingtothealpha1B-adrenoreceptor,thedissociationratewasincreased,indicatingnon-competitiveantagonismbyrho-TIA.N-terminallytruncatedanalogsofrho-TIAwerelessactivethanthefull-lengthpeptide,withalargedeclineinactivityobserveduponremovalofthefourthresidueofrho-TIA(Arg4).Analaninewalkofrho-TIAconfirmedtheimportanceofArg4foractivityandrevealedanumberofotherresiduesclusteredaroundArg4thatcontributetothepotencyofrho-TIA.Theuniqueallostericantagonismofrho-TIAresultingfromitsinteractionwithreceptorresiduesthatconstituteabindingsitethatisdistinctfromthatoftheclassicalcompetitivealpha1-adrenoreceptorantagonistsmayallowthedevelopmentofinhibitorsthatarehighlysubtypeselective.
SharpeI., etal. (2003) Allostericalpha1-AdrenoreceptorAntagonismbytheConopeptiderho-TIA. JBC.PMID:12824165
Subtype-selectivenoncompetitiveorcompetitiveinhibitionofhumanα1-Adrenergicreceptorsbyrho-TIA
The19-aminoacidconopeptide(rho-TIA)wasshownpreviouslytoantagonizenoncompetitivelyalpha(1B)-adrenergicreceptors(ARs).Becausethisisthefirstpeptideligandforthesereceptors,wecompareditsinteractionswiththethreerecombinanthumanalpha(1)-ARsubtypes(alpha(1A),alpha(1B),andalpha(1D)).Radioligandbindingassaysshowedthatrho-TIAwas10-foldselectiveforhumanalpha(1B)-overalpha(1A)-andalpha(1D)-ARs.Asobservedwithhamsteralpha(1B)-ARs,rho-TIAdecreasedthenumberofbindingsites(B(max))forhumanalpha(1B)-ARswithoutchangingaffinity(K(D)),andthisinhibitionwasunaffectedbythelengthofincubationbutwasreversedbywashing.However,rho-TIAhadoppositeeffectsathumanalpha(1A)-ARsandalpha(1D)-ARs,decreasingK(D)withoutchangingB(max),suggestingitactscompetitivelyatthesesubtypes.rho-TIAreducedmaximalNE-stimulated[(3)H]inositolphosphateformationinHEK293cellsexpressinghumanalpha(1B)-ARsbutcompetitivelyinhibitedresponsesincellsexpressingalpha(1A)-oralpha(1D)-ARs.Truncationmutantsshowedthattheamino-terminaldomainsofalpha(1B)-oralpha(1D)-ARsarenotinvolvedininteractionwithrho-TIA.Alanine-scanningmutagenesisofrho-TIAshowedF18Ahadanincreasedselectivityforalpha(1B)-ARs,andF18Nalsoincreasedsubtypeselectivity.I8Ahadaslightlyreducedpotencyatalpha(1B)-ARsandwasfoundtobeacompetitive,ratherthannoncompetitive,inhibitorinbothradioligandandfunctionalassays.Thusrho-TIAnoncompetitivelyinhibitsalpha(1B)-ARsbutcompetitivelyinhibitstheothertwosubtypes,andthisselectivitycanbeincreasedbymutation.Thesedifferentialinteractionsdonotinvolvethereceptoraminoterminiandarenotbecauseofthechargednatureofthepeptide,andisoleucine8iscriticalforitsnoncompetitiveinhibitionatalpha(1B)-ARs.
ChenZ., etal. (2004) Subtype-selectivenoncompetitiveorcompetitiveinhibitionofhuman α1-Adrenergicreceptorsbyrho-TIA. JBC.PMID:15194691
DifferentialDistributionofFunctionalalpha1-AdrenergicReceptorSubtypesalongtheRatTailArtery
Therattailarteryhasbeenusedforthestudyofvasoconstrictionmediatedbyalpha(1A)-adrenoceptors(ARs).However,ringsfromproximalsegmentsofthetailartery(withintheinitial4cm,PRTA)wereatleast3-foldmoresensitivetomethoxamineandphenylephrine(n=6-12;p<0.05)thanringsfromdistalparts(betweenthesixthand10thcm,DRTA).Interestingly,theimidazolinesN-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamidehydrobromide(A-61603)andoxymetazoline,whichactivateselectivelyalpha(1A)-ARs,wereequipotentinPRTAandDRTA(n=4-12),whereasbUSPirone,whichactivatesselectivelyalpha(1D)-AR,wasapproximately70-foldmorepotentinPRTAthaninDRTA(n=8;p<0.05).Theselectivealpha(1D)-ARantagonist8-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dionedihydrochloride(BMY-7378)wasapproximately70-foldmorepotentagainstthecontractionsinducedbyphenylephrineinPRTA(pK(B)ofapproximately8.45;n=6)thaninDRTA(pK(B)ofapproximately6.58;n=6),althoughtheantagonismwascomplexinPRTA.5-Methylurapidil,aselectivealpha(1A)-antagonist,wasequipotentinPRTAandDRTA(pK(B)ofapproximately8.4),buttheSchildslopeinDRTAwas0.73+/-0.05(n=5).Thenoncompetitivealpha(1B)-antagonistconotoxinrho-TIAreducedthemaximalcontractioninducedbyphenylephrineinDRTA,butnotinPRTA.Theseresultsindicateapredominantroleforalpha(1A)-ARsinthecontractionsofbothPRTAandDRTAbutwithsignificantcoparticipationsofalpha(1D)-ARsinPRTAandalpha(1B)-ARsinDRTA.Semiquantitativereversetranscription-polymerasechainreactionrevealedthatmRNAencodingalpha(1A)-andalpha(1B)-ARsaresimilarlydistributedinPRTAandDRTA,whereasmRNAforalpha(1D)-ARsistwicemoreabundantinPRTA.Therefore,alpha(1)-ARssubtypesaredifferentiallydistributedalongthetailartery.Itisimportanttoconsiderthesegmentfromwhichthetissuepreparationistakentoavoidmisinterpretationsonreceptormechanismsanddrugselectivities.
KamikiharaSY., etal. (2005) DifferentialDistributionofFunctionalalpha1-AdrenergicReceptorSubtypesalongtheRatTailArtery. JPET.PMID: 15872040
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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