Drosophila KCNQ Channel Displays Evolutionarily Conserved Electrophysiology and Pharmacology with Mammalian KCNQ Channels 英文参考文献.docVIP

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Drosophila KCNQ Channel Displays Evolutionarily Conserved Electrophysiology and Pharmacology with Mammalian KCNQ Channels 英文参考文献.doc

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Drosophila KCNQ Channel Displays Evolutionarily Conserved Electrophysiology and Pharmacology with Mammalian KCNQ Channels 英文参考文献

DrosophilaKCNQChannelDisplaysEvolutionarily ConservedElectrophysiologyandPharmacologywith MammalianKCNQChannels SoniaCavaliere,JamesJ.L.Hodge* UniversityofBristol,SchoolofPhysiologyandPharmacology,MedicalSciencesBuilding,Bristol,UnitedKingdom Abstract OfthefivehumanKCNQ(Kv7)channels,KCNQ1withauxiliarysubunitKCNE1mediatesthenativecardiacIKscurrentwith mutationscausingshortandlongQTcardiacarrhythmias.KCNQ4mutationscausedeafness.KCNQ2/3channelsformthe native M-current controlling excitability of most neurons, with mutations causing benign neonatal febrile convulsions. Drosophila contains a single KCNQ (dKCNQ) that appears to serve alone the functions of all the duplicated mammalian neuronalandcardiacKCNQchannelssharingroughly50–60%aminoacididentitythereforeofferingaroutetoinvestigate these channels.Currentinformationabout thefunctionalproperties ofdKCNQis lackingtherefore wehaveinvestigated thesepropertieshere.Usingwholecellpatchclampelectrophysiologywecomparethebiophysicalandpharmacological properties of dKCNQ with the mammalian neuronal and cardiac KCNQ channels expressed in HEK cells. We show that + DrosophilaKCNQ(dKCNQ)isaslowlyactivatingandslowly-deactivatingK currentopenatsub-thresholdpotentialsthat hassimilarpropertiestoneuronalKCNQ2/3withsomefeaturesofthecardiacKCNQ1/KCNE1accompaniedbyconserved sensitivity to a number of clinically relevant KCNQ blockers (chromanol 293B, XE991, linopirdine) and opener (zinc pyrithione).WealsoinvestigatethemolecularbasisofthedifferentialselectivityofKCNQchannelstotheopenerretigabine and show a single amino acid substitution (M217W) can confer sensitivity to dKCNQ. We show dKCNQ has similar electrophysiological and pharmacological properties as the mammalian KCNQ channels, allowing future study of physiological andpathologicalrolesofKCNQin Drosophila andwholeorganismscreening fornewmodulators of KCNQ channelopathies. Citation:CavaliereS,HodgeJJL(2011)DrosophilaKCNQChannelDisplaysEvolutionarilyConservedElectrophysio