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Toxicon48(2006)780–798ConotoxinsdownunderRaymondS.Nortona,,BaldomeroM.OliverabaWalterandElizaHallInstituteofMedicalResearch,1GRoyalParade,Parkville3050,Victoria,AustraliabDepartmentofBiology,UniversityofUtah,SaltLakeCity,UT84112,USAAvailableonline15July2006AbstractInthefourdecadessincetoxinologistsinAustraliaandelsewherestartedtoinvestigatetheactiveconstituentsofvenomousconesnails,awealthofinformationhasemergedonthevariousclassesofpeptidesandproteinsthatmaketheirvenomssuchpotentbioactivecocktails.Thisarticleprovidesanoverviewofthecurrentstateofknowledgeofthesevenomconstituents,severalofwhichareofinterestaspotentialhumantherapeuticsasaconsequenceoftheirhighpotencyandexquisitetargetspecificity.Withthepromiseofasmanyas50,000venomcomponentsacrosstheentireConusgenus,manymoreinterestingpeptidescanbeanticipated.r2006ElsevierLtd.Allrightsreserved.Keywords:Conesnail;Peptide;Ionchannel;Acetylcholinereceptor;Structure1.IntroductionThegenusConuscontainsaround500differentspeciesofpredatoryconesnails(Ro¨ckeletal.,1995)eachwithitsowndistinctive,complexandpeptide-richvenom.Venomisusedbythesecarnivorousmolluscsnotonlyastheprimaryweapontocaptureprey,butalsodefensivelyandcompetitively,aswellaspossiblyforotherfunctions(Olivera,1997).Conesnailsthriveprimarilyintropicalmarinehabitats(althoughafewspecieshavecolonizedcoolerwaters),andthecomplexwebofinteractionsinsuchmarinecommunitiesprovidesageneralratio-naleforwhyeachspecieshasevolveditsownlargeanddistinctmolecularrepertoireofvenomcompo-nents(Olivera,2002).Morethan100differentvenomcomponentsarefoundforeachConusspecies,leadingtoanestimateof450,000differentpharmacologicallyactivecomponentsinthegenusasawhole.Conusvenompeptidesareknowngenerallyasconopeptides,orcolloquiallyascon-otoxinsifdisulfide-rich.InaseparatearticleinthisSpecialIssueofToxicon,BarbaraHawgood(2006)describesthelifeandworkonBobEndean,oneofthegiantsofmarinetoxinologyinAustralia.AmongBob’smanyinterestswereconeshellvenoms,andduringthe1960sand1970sheinvestigatedtheactionsofarangeofConusspecies.Havingestablishedthatpiscivorous(fish-hunting)speciessuchasConusgeographus(thegeographycone),C.tulipa(tulipcone),C.catus(catcone),C.striatus(striatedcone)andC.magus(magician’sconeorConeofMaggi),ARTICLEINPRESS:10.1016/j.toxicon.2006.07.022Abbreviations:Ach,acetylcholine;Gla,g-carboxyglutamate;ICK,inhibitorycystineknot;nAChR,nicotinicacetylcholinereceptor;NMDA,N-methyl-D-aspartate;TTX,tetrodotoxin;VGSC,voltage-gatedsodiumchannelCorrespondingauthor.Fax:+61393470852.E-mailaddress:ray.norton@wehi.edu.au(R.S.Norton).werepotentiallythemostdangeroustoman,heproceededtocharacterizethepharmacologicalprofilesoftheirvenoms,layingthegroundworkformoredetailedstudiesbyothers,whichcontinuetoday.FurtheranalysisofthevenomofC.geographuswascarriedoutinthemid-1970sattheRocheResearchInstituteofMarinePharmacol-ogyinSydney(Spenceetal.,1977).Theseinvesti-gatorspurifiedthefirstpolypeptidecomponentofaConusvenom,andpresentedpharmacologicalevidenceconsistentwithdirectinhibitionofvol-tage-gatedNa+channels.ThefirstConusvenompeptideswerecharacter-izedbiochemicallyinthelate1970sandearly1980s(Cruzetal.,1978;Oliveraetal.,1985a),andthesystematicinvestigationofconesnailtoxinshascontinuedapaceeversince.Thisarticleprovidesanoverviewofourcurrentknowledgeofconotoxinsandconopeptides.SeveralgroupsinAustraliahavemade,andcontinuetomake,significantcontribu-tionstoourunderstandingofthisfascinatingarrayofpeptides,althoughinthisarticlewehavetriedtoprovideabroadoverviewratherthanfocusingonthecontributionsofindividuallabs.Anumberofconotoxinsandconopeptidesarepromisingleadsinthedevelopmentofnewtherapeuticsforuseinhumanmedicine(Livettetal.,2004).ThearticlebyLivettetal.(2006)inthisSpecialIssueexploresthisthemeinmoredetailfornicotinicacetylcholinereceptor(nAChR)antagonists,oneofwhichshowspotentialforthetreatmentofpain.Conusvenomcomponentscharacterizedtodatearepredominantlysmall,disulfide-crosslinkedpep-tidesthattargetionchannels,eitherligand-gatedorvoltage-gated.Indeed,mostConuspeptidesprob-ablyhaveaspecificionchannelasthephysiologi-callyrelevanttarget.Sincethesepredatorysnailsarenotendowedwithspeedormechanicalweaponry,theyhavecompensatedbyevolvingrapidly-acting,potentvenoms.Targetingionchannelsisapowerfulvenomstrategyinthiscontext,andtherichmoleculardiversityofpotentialionchanneltargetsisonefactorthathasledtomolecularcomplexityofpeptidesinconesnailvenoms.OthervenomcomponentstargetG-protein-coupledreceptorsandneurotransmittertransporters;someevenhaveenzymaticactivity.2.Biologyofconesnails:predatorsparexcellenceConesnailshaveavenomdeliverysystemconsistingofaduct,wherethevenomissynthesizedandstored,avenombulb,believedtoejectvenomfromtheduct,and,mostremarkably,hollow,harpoon-liketeethwhichserveasahypodermicneedleforinjectingthevenom(Fig.1).Mostconeshavealongdistensibleproboscis,and,whentheyforageforprey,asingleharpoontoothistrans-ferredintothelumenoftheproboscis.Oncetheextendedproboscistouchesprey,thetoo