Modulation of A(2a) receptor antagonist on D-2 receptor internalization and ERK phosphorylation

doi:10.1038/aps.2013.87

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第二研究室

	Modulation of A(2a) receptor antagonist on D-2 receptor internalization and ERK phosphorylation
	Huang, Li ; Wu, Dong-dong ; Zhang, Lei ; Feng, Lin-yin1,2
刊名	ACTA PHARMACOLOGICA SINICA
	2013-10
卷号	34 期号:10 页码:1292-1300
关键词	D-2 receptor A(2a) receptor striatum Parkinson's disease receptor heterodimerization receptor internalization Src kinase beta-arrestin ERK ZM241385
ISSN号	1671-4083
DOI	10.1038/aps.2013.87
文献子类	Article
英文摘要	Aim: To explore the effects of heterodimerization of D-2 receptor/A(2a) receptor (D2R/A(2a)R) on D2R internalization and D2R downstream signaling in primary cultured striatal neurons and HEK293 cells co-expressing A(2a)R and D2R in vitro. Methods: Primary cultured rat striatal neurons and HEK293 cells co-expressing A(2a)R and D2R were treated with A(2a)R- or D2R-specific agonists. D2R internalization was detected using a biotinylation assay and confocal microscopy. ERK, Src kinase and beta-arrestin were measured using Western blotting. The interaction between A(2a)R and D2R was detected using bioluminescence resonance energy transfer (BRET) and immunoprecipitation. Results: D2R and A(2a)R were co-localized and formed complexes in striatal neurons, while both the receptors formed heterodimers in the HEK293 cells. In striatal neurons and the HEK293 cells, the D2R agonist quinpirole (1 mu mol/L) marked increased Src phosphorylation and beta-arrestin recruitment, thereby D2R internalization. Co-treatment with the A(2a)R antagonist ZM241385 (100 nmol/L) significantly attenuated these D2R-mediated changes. Furthermore, both ZM241385 (100 nmol/L) and the specific Src kinase inhibitor PP2 (5 mu mol/L) blocked D2R-mediated ERK phosphorylation. Moreover, expression of the mutant beta-arrestin (319-418) significantly attenuated D2R-mediated ERK phosphorylation in HEK293 cells expressing both D2R and A(2a)R, but not in those expressing D2R alone. Conclusion: A(2a)R antagonist ZM241385 significantly attenuates D2R internalization and D2R-mediated ERK phosphorylation in striatal neurons, involving Src kinase and beta-arrestin. Thus, A(2a)R/D2R heterodimerization plays important roles in D2R downstream signaling.
资助项目	National Natural Science Foundation of China[81123004] ; Chinese Academy of Sciences[XDA01040304]
WOS关键词	PARKINSONS-DISEASE ; DOPAMINE-RECEPTORS ; BETA-ARRESTIN ; G-PROTEIN ; ISTRADEFYLLINE KW-6002 ; ACTIVATION ; CELLS ; NEURONS ; ROLES ; TRIAL
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:4935192
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000325276400005
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277441]
专题	药理学第二研究室
通讯作者	Feng, Lin-yin
作者单位	1.Chinese Acad Sci, Dept Neuropharmacol, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Huang, Li,Wu, Dong-dong,Zhang, Lei,et al. Modulation of A(2a) receptor antagonist on D-2 receptor internalization and ERK phosphorylation[J]. ACTA PHARMACOLOGICA SINICA,2013,34(10):1292-1300.
APA	Huang, Li,Wu, Dong-dong,Zhang, Lei,&Feng, Lin-yin.(2013).Modulation of A(2a) receptor antagonist on D-2 receptor internalization and ERK phosphorylation.ACTA PHARMACOLOGICA SINICA,34(10),1292-1300.
MLA	Huang, Li,et al."Modulation of A(2a) receptor antagonist on D-2 receptor internalization and ERK phosphorylation".ACTA PHARMACOLOGICA SINICA 34.10(2013):1292-1300.