Alpha-synuclein enhances dopamine D2 receptor signaling.
Parkinson's disease (PD) is characterized by a selective loss of dopamine-producing neurons in the substantia nigra (SN), which in turn results in dopamine depletion in the striatum, and the presence of neuronal cytoplasmic inclusions known as Lewy bodies (LBs). Alpha-synuclein is a presynaptic protein that accumulates abnormally in LBs and is seen predominantly in cases of dementia with LBs. Although the central role of alpha-synuclein in neurodegeneration has been previously demonstrated by the discovery of missense alpha-synuclein mutations in familial PD, the specific mechanism by which alpha-synuclein contributes to these diseases remains unclear. In the present study, we examined whether alpha-synuclein affects the downstream signaling of dopamine D2 receptor (D2R). In CHO cells stably transfected with D2Rs, alpha-synuclein enhanced dopamine D2-agonist-mediated inhibition of adenylate cyclase, which consequently affected its downstream cAMP-responsive element (CRE)-mediated gene transcription, while C-terminal deletion mutant of alpha-synuclein did not. Our study suggests that the alpha-synuclein enhances the dopamine-mediated intracellular signaling pathways by D2R, thus provide a possible mechanism in presynaptic regulation of the synaptic homeostasis in the dopaminergic neurotransmission.
Kim
Sung Jae
SJ
Molecular Neurobiology Laboratory, School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
Kim
Sung Yul
SY
Na
Young-Soon
YS
Lee
Hyun Jung
HJ
Chung
Kwang Chul
KC
Baik
Ja-Hyun
JH
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology; D004347:Drug Interactions; D015870:Gene Expression / Q000187:drug effects; D008156:Luciferases / Q000378:metabolism; D009154:Mutation / Q000502:physiology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection / Q000379:methods; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D010446:Peptide Fragments; D017448:Receptors, Dopamine D2; D051844:alpha-Synuclein; D005576:Colforsin; D000242:Cyclic AMP; D008156:Luciferases; D004298:Dopamine