α-conotoxinPIAhasbeenisolatedfromthevenomofthemarinesnailConuspurpurascens.α-conotoxinPIApreferentiallytargetsneuronalAChRsubtypescontainingα6subunits.Thepeptidedisplays75-foldhigheraffinityforratα6/α3β2β3nAChRsoverratα3β2nAChRs.α-conotoxinPIApotentlyinhibitshumanchimericα6/α3β2β3nAChRs(IC50of1.7nM)andprovidedsimilarresultsonratchimericα6/α3β2β3(IC50of0.95nM).10μMα-conotoxinPIAhasnoeffectontheadultformofthehumanmusclenAChRdemonstratingahighspecificityforα6-containingneuronalnAChRs.Thepeptidehasnoeffectonα2-andα4-containingneuronalnAChRs.α6-containingneuronalnAChRsarehighlyexpressedinseveralcatecholaminergicnuclei(locuscoeruleus,ventraltegmentalareaandsubstantianigra),playasignificantroleinnicotinicrewardanddependence,andisatherapeutictargetofinterestinParkinsondisease.
Description:
AAsequence:RDPCCSNPVCTVHNPQIC-NH2
Disulfidebonds:Cys4-Cys10andCys5-Cys18
Formula:C79H125N27O25S4
MolecularWeight:1981.29g/mol
Appearance:Whitelyophilizedsolid
Solubility: waterorsalinebuffer
Source: Synthetic
Purityrate: >95%
Reference:
ConotoxinPIAIsSelectiveforα6Subunit-ContainingNicotinicAcetylcholineReceptors
Untilnow,therehavebeennoantagoNISTstodiscriminatebetweenheteromericnicotinicacetylcholinereceptors(nAChRs)containingtheverycloselyrelatedα6andα3subunits.nAChRscontainingα3,α4,orα6subunitsincombinationwithβ2,occasionallyβ4,andsometimesβ3orα5subunits,arethoughttoplayimportantrolesincognitivefunction,painperception,andthereinforcingpropertiesofnicotine.WeclonedanovelgenefromthepredatorymarinesnailConuspurpurascens.Thepredictedpeptide,α-conotoxinPIA,potentlyblocksthechimericα6/α3β2β3subunitcombinationasexpressedinoocytesbutneitherthemusclenorthemajorneuronalnAChRα4β2.Additionally,thistoxinisthefirstdescribedligandtodiscriminatebetweennAChRscontainingα6andα3subunits.Exploitingtheunusualintronconservationofconotoxingenesmayrepresentamoregeneralapproachfordefiningconotoxinligandscaffoldstodiscriminateamongcloselyrelatedreceptorpopulations.