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Smartox/Selective blocker of Nav1.4 channels/CON021-00100/0.1mg
µ-conotoxinCnIIICisaconopeptidethathasbeenisolatedfromthevenomofthemarineconesnail Conusconsors. µ-conotoxinCnIIICexhibitsamyorelaxingeffectthroughspecificblockadeoftheskeletalmuscle Nav1.4channels (IC50 =1.4nM). µ-conotoxinCnIIIC alsoblocks Nav1.2channels (1µM)andmildlyNav1.7.Incontrast,Nav1.5andNav1.8areinsensitivetotheactionofthetoxin. µ-conotoxinCnIIIC alsoblocksthe α3β2nicotinicacetylcholinereceptor (IC50=450nM)andtolesserextentstheα7andα4β2subtypes. µ-conotoxinCnIIIC completelyinhibitstwitchtensioninisolatedmousehemidiaphragms(IC50 =150nM).
Description:
AAsequence:Pyr-Gly-Cys3-Cys4-Asn-Gly-Pro-Lys-Gly-Cys10-Ser-Ser-Lys-Trp-Cys15-Arg-Asp-His-Ala-Arg-Cys21-Cys22-NH2
Disulfidebonds:Cys3-Cys15,Cys4-Cys21 andCys10-Cys22
Length(aa): 22
Formula:C92H141N35O28S6
MolecularWeight:2375.8Da
Appearance:Whitelyophilizedsolid
Solubility:waterandsalinebuffer
CASnumber:
Source:Synthetic
Purityrate:>97%
Reference:
Anovelµ-conopeptide,CnIIIC,exertspotentandpreferentialinhibitionofNaV1.2/1.4channelsandblocksneuronalnicotinicacetylcholinereceptors
BACKGROUNDANDPURPOSE:
Theµ-conopeptidefamilyisdefinedbyitsABIlitytoblockvoltage-gatedsodiumchannels(VGSCs),apropertythatcanbeusedforthedevelopmentofmyorelaxantsandanalgesics.Wecharacterizedthepharmacologyofanewµ-conopeptide(µ-CnIIIC)onarangeofpreparationsandmoleculartargetstoassessitspotentialasamyorelaxant.
EXPERIMENTALAPPROACH:
µ-CnIIICwassequenced,synthesizedandcharacterizedbyitsdirectblockofelicitedtwitchtensioninmouseskeletalmuscleandactionpotentialsinmousesciaticandpikeolfactorynerves.µ-CnIIICwasalsostudiedonHEK-293cellsexpressingvariousrodentVGSCsandalsoonvoltage-gatedpotassiumchannelsandnicotinicacetylcholinereceptors(nAChRs)toassesscross-interactions.Nuclearmagneticresonance(NMR)experimentswerecarriedoutforstructuraldata.
KEYRESULTS:
Syntheticµ-CnIIICdecreasedtwitchtensioninmousehemidiaphragms(IC(50)=150nM),anddisplayedahigherblockingeffectinmouseextensordigitorumlongusmuscles(IC=46nM),comparedwithµ-SIIIA,µ-SmIIIAandµ-PIIIA.µ-CnIIICblockedNa(V)1.4(IC(50)=1.3nM)andNa(V)1.2channelsinalong-lastingmanner.CardiacNa(V)1.5andDRG-specificNa(V)1.8channelswerenotblockedat1µM.µ-CnIIICalsoblockedtheα3β2nAChRsubtype(IC(50)=450nM)and,toalesserextent,ontheα7andα4β2subtypes.Structuredeterminationofµ-CnIIICrevealedsomesimilaritiestoα-conotoxinsactingonnAChRs.
CONCLUSIONANDIMPLICATIONS:
µ-CnIIICpotentlyblockedVGSCsinskeletalmuscleandnerve,andhenceisapplicabletomyorelaxation.ItsatypicalpharmacologicalprofilesuggestssomecommonstructuralfeaturesbetweenVGSCsandnAChRchannels.
FavreauP.,etal.(2012)Anovelµ-conopeptide,CnIIIC,exertspotentandpreferentialinhibitionofNaV1.2/1.4channelsandblocksneuronalnicotinicacetylcholinereceptors.BJP.PMID:22229737
Mechanismandmolecularbasisforthesodiumchannelsubtypespecificityofµ-conopeptideCnIIIC.
BACKGROUNDANDPURPOSE
Voltage-gatedsodiumchannels(Na(V)channels)arekeyplayersinthegenerationandpropagationofactionpotentials,andselectiveblockadeofthesechannelsisapromisingstrategyforclinicallyusefulsuppressionofelectricalactivity.Theconotoxinµ-CnIIICfromtheconesnailConusconsorsexhibitsmyorelaxingactivityinrodentsthroughspecificblockadeofskeletalmuscle(Na(V)1.4)Na(V)channels.
EXPERIMENTALAPPROACH:
Weinvestigatedtheactivityofµ-CnIIIConhumanNa(V)channelsandcharacterizeditsinhibitorymechanism,aswellasthemolecularbasis,foritschannelspecificity.
KEYRESULTS:
Similartoratparalogs,humanNa(V)1.4andNa(V)1.2werepotentlyblockedbyµ-CnIIIC,thesensitivityofNa(V)1.7wasintermediate,andNa(V)1.5andNa(V)1.8wereinsensitive.Half-channelchimerasrevealedthatdeterminantsfortheinsensitivityofNa(V)1.8mustresideinboththefirstandsecondhalvesofthechannel,whilethoseforNa(V)1.5arerestrictedtodomainsIandII.FurThermore,domainIporeloopaffectedthetotalblockandthereforeharboursthemajordeterminantsforthesubtypespecificity.DomainIIporelooponlyaffectedthekineticsoftoxinbindinganddissociation.Blockadebyµ-CnIIICofNa(V)1.4wasvirtuallyirreversIBLebutleftaresidualcurrentofabout5%,reflectinga‘leaky’block;therefore,Na(+)ionsstillpassedthroughµ-CnIIIC-occupiedNa(V)1.4tosomeextent.TTXwasexcludedfromthisbindingsitebutwastrappedinsidetheporebyµ-CnIIIC.
CONCLUSIONANDIMPLICATIONS:
Ofclinicalsignificance,µ-CnIIICisapotentandpersistentblockerofhumanskeletalmuscleNa(V)1.4thatdoesnotaffectactivityofcardiacNa(V)1.5.
MarkgrafR.,etal.(2012)Mechanismandmolecularbasisforthesodiumchannelsubtypespecificityofµ-conopeptideCnIIIC.BJP.PMID:22537004
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