α-conotoxinGI (alpha-conotoxinGI)isaconopeptidethathasbeenisolatedfromthevenomoftheconesnailConusgeographus.α-conotoxinGIisacompetitiveantagoNISTofthemuscle-typenicotinicacetylcholinereceptors(nAChR)suchas α-conotoxinMIord-Turbocurarine. α-conotoxinGIallowstodistinguishbetweenthetwoagonistsitesasitbinds10,000-foldmoretightlytotheα/δthantotheα/γsiteexceptedinTorpedowhichisthereverse.
Description:
AAsequence: Glu-Cys2-Cys3-Asn-Pro-Ala-Cys7-Gly-Arg-His-Tyr-Ser-Cys13-NH2
Disulfidebonds: Cys2-Cys7,Cys3-Cys13
Length(aa): 13
Formula: C55H80N20O18S4
MolecularWeight: 1437.61Da
Appearance: Whitelyophilizedsolid
Solubility: waterorsalinebuffer
CASnumber: [76862-65-2]Source: Synthetic
Purityrate: >95%
Reference:
Determinantsinvolvedintheaffinityofalpha-conotoxinsGIandSIforthemusclesubtypeofnicotinicacetylcholinereceptors
Nicotinicacetylcholinereceptorsfrommusclecontaintwofunctionallyactiveandpharmacologicallydistinctacetylcholine-bindingsiteslocatedatthealpha/gammaandalpha/deltasubunitinterfaces.Thealpha-conotoxinsarecompetitiveantagonistsofnicotinicreceptorsandcanbehighlysite-selective,displayinggreaterthan10,000-folddifferencesinaffinitiesforthetwoacetylcholine-bindingsitesonasinglenicotinicreceptor.Thehigheraffinitysiteforalpha-conotoxinsGI,MI,andSIisthealpha/deltasiteonmousemuscle-derivedBC3H-1receptors.However,alpha-conotoxinsGIandMIexhibithigheraffinityfortheothersite(alpha/gammasite)onnicotinicreceptorsfromTorpedocalifornicaelectricorgan.alpha-ConotoxinSIdoesnotdistinguishbetweenthetwoacetylcholine-bindingsitesonTorpedoreceptors.Inthisstudy,alpha-conotoxins[K10H]SIand[K10N]SIdisplayedwild-typeaffinityforthetwoacetylcholine-bindingsitesonBC3H-1receptorsbuta10-20-folddecreaseinapparentaffinityatoneofthetwoacetylcholine-bindingsitesonTorpedoreceptors.alpha-Conotoxin[P9K]SIdisplayedaselectiveanddramaticincreaseintheapparentaffinityforthealpha/deltasiteofBC3H-1receptorsandforthealpha/gammasiteofTorpedoreceptors.alpha-Conotoxin[R9A]GIdisplayedareductioninaffinityforbothacetylcholine-bindingsitesonBC3H-1receptors,althoughtheextentofitsselectivityforthealpha/deltasitewasretained.alpha-Conotoxin[R9A]GIalsodisplayedalossofaffinityforthetwoacetylcholine-bindingsitesonTorpedoreceptors,butitssite-selectivitywasapparentlyabolished.Theseresultsindicatethatpositions9and10inalpha-conotoxinsGIandSIareinvolvedincomplexspecies-andsubunit-dependentinteractionswithnicotinicreceptors.
Groebe,DR., etal. (1997)Determinantsinvolvedintheaffinityofalpha-conotoxinsGIandSIforthemusclesubtypeofnicotinicacetylcholinereceptors, Biochemistry. PMID:9174364
Alpha-ConotoxinGIproducestetanicfadeattheratneuromuscularjunction
TheABIlityofthemarinesnailtoxin,alpha-conotoxinGI,toproduceblockadeofsinglyevokedtwitchesandtoproducetetanicandtrain-of-fourfadehasbeendeterminedintheisolatedrathemidiaphragmpreparation.ResultswerecomparedtothoseobtainedwithareversIBLe(vecuronium)andanirreversible(alpha-bungarotoxin)nicotinicacetylcholineantagonistandhavebeeninterpretedintermsofrelativeeffectsonpost-andprejunctionalnicotinicacetylcholinereceptorsattheneuromuscularjunction.alpha-ConotoxinGI(0.5-2microM)producedaconcentration-dependent,reADIlyreversible,decreaseinthepeakamplitudeofsingletwitchesand50Hztetani,andanincreaseintetanicandtrain-of-fourfade.alpha-ConotoxinGIwasconsistently2-3-foldmorepotentthanvecuroniumwithrespecttoallofthemeasuredtensionparameters.Bothalpha-conotoxinGIandvecuroniumwereapproximately2-foldmorepotentinproducingtetanicfadeandinblockingtetaniccontractionsthaninblockingsingletwitches.Incontrasttobothalpha-conotoxinGIandvecuronium,alpha-bungarotoxin(0.13microM)reducedthepeakamplitudeofbothsingletwitchesand50Hztetanitothesameextentwithouttheappearanceofalargedegreeoftetanicortrain-of-fourfade.Basedonacomparisonoftheinvitrotimecourseofneuromuscularblockandoftherelativeeffectsofvecuronium,alpha-conotoxinGIandalpha-bungarotoxinontwitches,tetaniandtrains-of-four,weconcludethatalpha-conotoxinGIhasbothpre-andpostjunctionalactivityattheneuromuscularjunction.Inthisrespect,alpha-conotoxinGIresemblestheclinicallyusedcompetitiveneuromuscularblockingdrugsratherthantheirreversiblesnakealpha-neurotoxins.
BlountK., etal.(1992)Alpha-ConotoxinGIproducestetanicfadeattheratneuromuscularjunction. Toxicon. PMID:1355934
PostsynapticblockoffrogneuromusculartransmissionbyconotoxinGI
ConotoxinGI,apeptideneurotoxincontainedinthevenomofthemarinesnailConusgeographus,wasappliedtothecutaneouspectorismuscleofthefrog,andtheeffectsonthepostsynapticresponsetoacetylcholinewereexamined.ConotoxinGIreversiblyblockednerve-evokedmusclecontractionsatconcentrationsgreaterthanorequalto3to4microM.MicromolarconcentrationsofconotoxinGIsignificantlyreducedtheamplitudeofminiatureendplatepotentialsandmembranedepolarizationsproducedbyionophoreticapplicationofacetylcholine,suggestingthatthetoxinreducedthepostsynapticsensitivitytoacetylcholine.Thereductioninthesensitivityofthemuscletoacetylcholinewasnotduetochangesinmusclefiberrestingmembranepotentialorinputresistance.ConotoxinGIreducedtheamplitudesbutdidnotaffecttheratesofdecayoffocal,extracellularlyrecordedendplatecurrentsorminiatureendplatecurrents,suggestingthatthetoxindidnotaffectthelifetimeofionchannelsopenedbyacetylcholine.Miniatureendplatecurrentsdecayfivetosixtimesmoreslowlythannormalwhenacetylcholinesteraseisblockedwithneostigminemethylsulfateduetorepeatedbindingofacetylcholinetoreceptorsasitdiffusesfromthesynapticcleft.ConotoxinGIreducedtheamplitudeandincreasedtherateofdecayofminiatureendplatecurrentsrecordedinthepresenceofneostigminemethylsulfate,suggestingthatthetoxinreducedthebindingofacetylcholinetoendplatereceptors.TheseresultsareconsistentwiththehypothesisthatconotoxinGIblocksneuromusculartransmissionatthefrogendplatebyreducingthebindingofacetylcholinetoreceptors.
McManusOB., etal.(1985)PostsynapticblockoffrogneuromusculartransmissionbyconotoxinGI. JNeurosci. PMID:2981295
PeptidesisolatedfromthevenomofConusgeographusblockneuromusculartransmission
Theeffectsofamixtureoftwopeptides(GIandGII),purifiedfromthevenomofthemarinegastropod,Conusgeographus,werestudiedonneuromusculartransmissionintheisolatedmousephrenicnerve–diaphragmandfrogsciaticnerve–sartoriusmuscles.TheGI–GIImixturerapidlyblockednerve-evokedcontractionsofthemousediaphragmatbathconcentrationsgreaterthanorequalto0.2microMbuthadnoeffectoncontractionselicitedbydirectmusclestimulation.ParalyticconcentrationsofGI–GIIhadnosignificanteffectonthecompoundnerveactionpotentialofthebullfrogsciaticnerve.SimilarconcentrationsofGI–GIIproducedarapidreductionofendplatepotential(epp)andminiatureendplatepotentialamplitudes,apparentlybyapostsynapticeffectbecausethedecreaseineppamplitudeproducedbysubparalyticdoseswasnotaccompaniedbysignificantalterationintheeppquantalcontent.TheGI–GIImixturealsoinhibited[125I]alpha-bungarotoxinbindingtoendplateregionsofthemousediaphragminadose-dependentmannerandwasatleast10timesmorepotentthand-tubocurarine.WeconcludethattheblockageofvertebrateneuromusculartransmissionbyGI–GIIisinpartduetoantagonismofacetylcholinebindingtoitsreceptoratmotorendplates.
McManusOB., etal. (1981)PeptidesisolatedfromthevenomofConusgeographusblockneuromusculartransmission.NeurosciLett. PMID:6269031
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