Adenylyl Cyclases 1 and 8 Initiate a Presynaptic Homeostatic Response to Ethanol Treatment 英文参考文献.docVIP

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Adenylyl Cyclases 1 and 8 Initiate a Presynaptic Homeostatic Response to Ethanol Treatment 英文参考文献.doc

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Adenylyl Cyclases 1 and 8 Initiate a Presynaptic Homeostatic Response to Ethanol Treatment 英文参考文献

AdenylylCyclases1and8InitiateaPresynaptic HomeostaticResponsetoEthanolTreatment AlanaC.Conti1*,JamesW.Maas,Jr1,KristaL.Moulder3,XiaopingJiang3,BhumyA.Dave1, StevenMennerick3,4,LouisJ.Muglia1,2 1Department of Pediatrics, Washington University in St. Louis, St. Louis, Missouri, United States of America, 2Department of Molecular Biology and Pharmacology, WashingtonUniversityinSt.Louis,St.Louis,Missouri,UnitedStatesofAmerica,3DepartmentofPsychiatry,WashingtonUniversityinSt.Louis,St.Louis,Missouri,United StatesofAmerica,4DepartmentofAnatomyandNeurobiology,WashingtonUniversityinSt.Louis,St.Louis,Missouri,UnitedStatesofAmerica Abstract Background: Although ethanol exerts widespread action in the brain, only recently has progress been made in understanding the specific events occurring at the synapse during ethanol exposure. Mice deficient in the calcium- stimulatedadenylylcyclases,AC1andAC8(DKO),demonstrateincreasedsedationdurationandimpairedphosphorylation byproteinkinaseA(PKA)followingacuteethanoltreatment.Whilenotdirecttargetsforethanol,wehypothesizethatthese cyclasesinitiateahomeostaticpresynapticresponsebyPKAtoreactivateneuronsfromethanol-mediatedinhibition. Methodology/Principal Findings: Here, we have used phosphoproteomic techniques and identified several presynaptic proteinsthatarephosphorylatedinthebrainsofwildtypemice(WT)afterethanolexposure,includingsynapsin,aknown PKA target. Phosphorylation of synapsins I and II, as well as phosphorylation of non-PKA targets, such as, eukaryotic elongationfactor-2(eEF-2)anddynaminissignificantlyimpairedinthebrainsofDKOmice.Thisdeficitisprimarilydrivenby AC1,asAC1-deficient,butnotAC8-deficientmicealsodemonstratesignificantreductionsinphosphorylationofsynapsin andeEF-2incorticalandhippocampaltissues.DKOmicehaveareducedpooloffunctionalrecyclingvesiclesandfewer active terminals as measured by FM1-43 uptake compared to WT controls, which may be a contributing factor to the impairedpresynapticresponsetoethanoltreatment. Conclusio