A PI3-Kinase–Mediated Negative Feedback Regulates Neuronal Excitability 英文参考文献.docVIP

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A PI3-Kinase–Mediated Negative Feedback Regulates Neuronal Excitability 英文参考文献.doc

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A PI3-Kinase–Mediated Negative Feedback Regulates Neuronal Excitability 英文参考文献

API3-Kinase–MediatedNegativeFeedbackRegulates NeuronalExcitability EricHowlett*,CurtisChun-JenLin,WilliamLavery,MichaelStern DepartmentofBiochemistryandCellBiology,RiceUniversity,Houston,Texas,UnitedStatesofAmerica Abstract Use-dependentdownregulationofneuronalactivity(negativefeedback)canactasahomeostaticmechanismtomaintain neuronalactivityataparticularspecifiedvalue.Disruptionofthisnegativefeedbackmightleadtoneurologicalpathologies, suchasepilepsy,buttheprecisemechanismsbywhichthisfeedbackcanoccurremainincompletelyunderstood.Atone glutamatergicsynapse,theDrosophilaneuromuscularjunction,amutationinthegroupIImetabotropicglutamatereceptor gene(DmGluRA)increasedmotorneuronexcitabilitybydisrupting anautocrine,glutamate-mediatednegativefeedback. We show that DmGluRA mutations increase neuronal excitability by preventing PI3 kinase (PI3K) activation and consequently hyperactivating the transcription factor Foxo. Furthermore, glutamate application increases levels of phospho-Akt,aproductofPI3Ksignaling,withinmotornerveterminalsinaDmGluRA-dependentmanner.Finally,weshow thatPI3KincreasesbothaxondiameterandsynapsenumberviatheTor/S6kinasepathway,butnotFoxo.Inhumans,PI3K andgroupIImGluRsareimplicatedinepilepsy,neurofibromatosis,autism,schizophrenia,andotherneurologicaldisorders; however, neither the link between group II mGluRs and PI3K, nor the role of PI3K-dependent regulation of Foxo in the control of neuronal excitability, had been previously reported. Our work suggests that some of the deficits in these neurologicaldisordersmightresultfromdisruptionofglutamate-mediatedhomeostasisofneuronalexcitability. Citation:HowlettE,LinCC-J,LaveryW,SternM(2008)API3-Kinase–MediatedNegativeFeedbackRegulatesNeuronalExcitability.PLoSGenet4(11):e1000277. doi:10.1371/journal.pgen.1000277 Editor:WayneN.Frankel,TheJacksonLaboratory,UnitedStatesofAmerica ReceivedJuly9,2008;AcceptedOctober23,2008;PublishedNovember28,2008 Copyright: ? 2008 Howlett et al. This is an open-access article distr