Dopamine Inhibits Mitochondrial Motility in Hippocampal Neurons 英文参考文献.docVIP

DopamineInhibitsMitochondrialMotilityin HippocampalNeurons SigengChen,GeoffreyC.Owens,DavidB.Edelman* TheNeurosciencesInstitute,SanDiego,California,UnitedStatesofAmerica Abstract Background:Thetraffickingofmitochondriawithinneuronsisahighlyregulatedprocess.Inanearlierstudy,wefoundthat serotonin (5-HT), acting through the 5-HT1A receptor subtype, promotes axonal transport of mitochondria in cultured hippocampalneuronsbyincreasingAktactivity,andconsequentlydecreasingglycogensynthasekinase(GSK3b )activity. This finding suggests a critical role for neuromodulators in the regulation of mitochondrial trafficking in neurons. In the presentstudy,weinvestigatetheeffectsofasecondimportantneuromodulator,dopamine,onmitochondrialtransportin hippocampalneurons. Methodology/Principal Findings: Here, we show that dopamine, like 5-HT, regulates mitochondrial motility in cultured hippocampal neurons through the Akt-GSK3b signaling cascade. But, in contrast to the stimulatory effect of 5-HT, administration of exogenous dopamine or bromocriptine, a dopamine 2 receptor (D2R) agonist, caused an inhibition of mitochondrial movement. Moreover, pretreatment with bromocriptine blocked the stimulatory effect of 5-HT on mitochondrialmovement.Conversely,incellspretreatedwith5-HT,nofurtherincreasesinmovementwereobservedafter administration of haloperidol, a D2R antagonist. In contrast to the effect of the D2R agonist, addition of SKF38393, a dopamine1receptor(D1R)agonist,promotedmitochondrialtransport,indicatingthattheinhibitoryeffectofdopamine was actually the net summation of opposing influences of the two receptor subtypes. The most pronounced effect of dopamine signals was on mitochondria that were already moving directionally. Western blot analysis revealed that treatmentwitheitheraD2RagonistoraD1RantagonistdecreasedAktactivity,andconversely,treatmentwitheitheraD2R antagonistoraD1RagonistincreasedAktactivity. Conclusions/Significance: Our observations strongly suggest a role for both dopa