Mutational Analysis of the Analgesic Peptide DrTx(1-42) Revealing a Functional Role of the Amino-Terminal Turn 英文参考文献.docVIP

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Mutational Analysis of the Analgesic Peptide DrTx(1-42) Revealing a Functional Role of the Amino-Terminal Turn 英文参考文献.doc

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Mutational Analysis of the Analgesic Peptide DrTx(1-42) Revealing a Functional Role of the Amino-Terminal Turn 英文参考文献

MutationalAnalysisoftheAnalgesicPeptideDrTx(1-42) RevealingaFunctionalRoleoftheAmino-TerminalTurn PingLi,ShunyiZhu* StateKeyLaboratoryofIntegratedManagementofPestInsectsandRodents,InstituteofZoology,ChineseAcademyofSciences,Beijing,People’sRepublicofChina Abstract Background: DrTx(1-42) (a carboxyl-terminally truncated version of drosotoxin) is a potent and selective blocker of tetrodotoxin-resistant(TTX-R)Na channelsinratdorsalrootganglionneuronswithanalgesicactivity.Thispurposeisto identifykeyaminoacidswhichareresponsibleforbothblockingandanalgesiceffectsofDrTx(1-42). + Methods:Onthebasisofpreviousstudy,wedesignedfivemutantsofDrTx(1-42)(delN,D8A,D8K,G9A,andG9R)inthe amino-terminalturn(N-turn)region,aproposedfunctionalregionlocatedintheamino-terminusofthemolecule.Allthese mutants were expressed in E.coli and purified by RP-HPLC. Electrophysiological properties of these analogues were examinedbywhole-cellpatch-clamprecordingsandtheirantinociceptiveeffectswereinvestigatedbytheformalintestand aceticacidinducedwrithingtest. Results:AllthemutantsexceptforG9ApossessasimilarsecondarystructuretothatofDrTx(1-42),asidentifiedbycircular dichroismanalysis.Threemutants(delN,D8AandG9A)werefoundalmostinactivetoTTX-RNa channels,whereasD8K + retainssimilaractivityandG9Rshoweddecreasedpotencywhencomparedwiththewild-typemolecule.Consistentwith the electrophysiological observations, D8K and G9R exhibited antinociceptive effects in the second phase (inflammatory pain)oftheformalintestandtheaceticacidinducedwrithingtest,whiledelN,D8AandG9Alacksucheffects. Conclusions:OurresultsshowthattheN-turniscloselyrelatedtofunctionofDrTx(1-42).Themutant(D8A)asacontrol peptidefurtherrevealsthatachargedresidueatsite8oftheN-terminusisimportantforchannelblockadeandanalgesic + activity. This study indicates that blocking of voltage-gated TTX-R Na channel in DRG neurons contributes to analgesic effectinratinflammatorypain.Structuralandfunctionaldatadescribedhereofferssupportforthedevelopmentof