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商品描述
Hm1ahasbeenidentifiedfromthevenomofthespiderHeteroscodramaculata.Hm1ahasbeendescribedasapotentandselectiveagoNISTofthevoltage-gatedsodiumchannelNav1.1withanECvalueof38nM.Nav1.1isexpressedintheCNSandmutationsareassociatedwithseveraldisorderssuchasepilespyorautism.
SmartoxBiotechnologyispleasedtoofferasyntheticandfunctionallyactiveHm1adedicatedtoresearchlaboratoryuseonly.
Description:
AAsequence:ECRYLFGGCSSTSDCCKHLSCRSDWKYCAWDGTFS-OH
Disulfidebonds: Cys2-Cys16,Cys9-Cys21,Cys15-Cys28
Length(aa): 35
Formula: C170H239N47O54S6
MolecularWeight: 3997.46g/mol
CASnumber:
Source: Synthetic
Purityrate: >95%
Reference:
Voltage-gatedsodium(Nav)channelsinitiateactionpotentialsinmostneurons,includingprimaryafferentnervefibresofthepainpathway.Localanaestheticsblockpainthroughnon-specificactionsatallNavchannels,butthediscoveryofselectivemodulatorswouldfacilitatetheanalysisofindividualsubtypesofthesechannelsandtheircontributionstochemical,mechanical,orthermalpain.Hereweidentifyandcharacterizespider(Heteroscodramaculata)toxinsthatselectivelyactivatetheNav1.1subtype,theroleofwhichinnociceptionandpainhasnotbeenelucidated.WeusetheseprobestoshowthatNav1.1-expressingfibresaremodality-specificnociceptors:theiractivationelicitsrobustpainbehaviourswithoutneurogenicinflammationandproducesprofoundhypersensitivitytomechanical,butnotthermal,stimuli.Inthegut,high-thresholdmechanosensitivefibresalsoexpressNav1.1andshowenhancedtoxinsensitivityinamousemodelofirritablebowelsyndrome.Together,thesefindingsestablishanunexpectedroleforNav1.1channelsinregulatingtheexcitABIlityofsensorynervefibresthatmediatemechanicalpain.
TheNav1.1voltage-gatedsodiumchannelisacriticalcontributortoexcitabilityinthebrain,wherepathologicallossoffunctionleadstosuchdisordersasepilepsy,Alzheimer’sdisease,andautism.Thisvoltage-gatedsodium(Nav)channelsubtypealsoplaysanimportantroleinmechanicalpainsignalingbyprimaryafferentsomatosensoryneurons.Therefore,pharmacologicmodulationofNav1.1representsapotentialstrategyfortreatingexcitabilitydisordersofthebrainandperiphery.InactivationisacomplexaspectofNavchannelgatingandconsistsoffastandslowcomponents,eachofwhichmayinvolveacontributionfromoneormorevoltage-sensingdomains.Here,weexploittheHm1aspidertoxin,aNav1.1-selectivemodulator,tobetterunderstandtherelationshipbetweenthesetemporallydistinctmodesofinactivationandaskwhethertheycanbedistinguishedpharmacologically.WeshowthatHm1ainhibitsthegatingmovementofthedomainIVvoltagesensor(VSDIV),hinderingbothfastandslowinactivationandleADIngtoanincreaseinNav1.1availabilityduringhigh-frequencystimulation.Incontrast,ICA-121431,asmall-moleculeNav1.1inhibitor,acceleratesasubsequentVSDIVgatingtransitiontoaccelerateentryintotheslowinactivatedstate,resultinginuse-dependentblock.FurtherevidenceforfunctionalcouplingbetweenfastandslowinactivationisprovidedbyaNav1.1mutantinwhichfastinactivationremovalhascomplexeffectsonslowinactivation.Takentogether,ourdatasubstantiatethekeyroleofVSDIVinNavchannelfastandslowinactivationanddemonstratethatthesegatingprocessesaresequentialandcoupledthroughVSDIV.ThesefindingsprovideinsightintoapharmacophoreonVSDIVthroughwhichmodulationofinactivationgatingcaninhibitorfacilitateNav1.1function.
