Venom-derivedpeptidemodulatorsof ion channelgatingareregardedasessentialtoolsforunderstandingthemolecularmotionsthatoccurduringtheopeningandclosingof ion channels.Inthisstudy,wepresentthecharacterizationoffivespidertoxinson12humanvoltage-gated ion channels,followingobservationsaboutthe target promiscuity ofsomespidertoxinsandtheongoingrevisionoftheir“canonical”gating-modifyingmodeofaction.The peptides werepurifieddenovofromthe venom ofGrammostolaroseatarantulas,andtheirsequenceswereconfirmedbyEdmandegradationandmassspectrometryanalysis.Their effects onseventetrodotoxin-sensitive Na(+) channels,thethreehumanether-à-go-go(hERG)-related K(+) channels,andtwohumanShaker-related K(+) channels wereextensivelycharacterizedbyelectrophysiologicaltechniques.Allthepeptides inhibited ion conductionthroughallthe Na(+) channels tested,althoughwithdistinctivepatterns.The peptides alsoaffectedthethreepharmaceuticallyrelevanthERGisoformsdifferently.Athigherconcentrations,all peptides alsomodifiedthegatingofthe Na(+) channels byshiftingtheactivationtomorepositivepotentials,whereasmorecomplex effects wererecordedonhERG channels.No effects wereevidentonthetwoShaker-related K(+) channels atconcentrationswellabovetheIC(50)valuefortheaffected channels.Giventhesequencediversityofthetestedpeptides,weproposethat tarantula toxinsshouldbeconsideredbothasmultimodeand target-promiscuous ion channelmodulators;bothfeaturesshouldnotbeignoredwhenextractingmechaNISTicinterpretationsabout ion channelgating.Ourobservationscouldalsoaidinfuturestructure-functionstudiesandmighthelpthedevelopmentofnovel ion channel-specificdrugs.

ELISARedaelli,etal.(2010)TargetPromiscuityandHeterogeneousEffectsofTarantulaVenomPeptidesAffectingNa⁺ andK⁺ IonChannels. JBC. PMID: 19955179