期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 394, 期 4, 页码 988-992出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2010.03.104
关键词
Dopamine D-2 receptor; Adenosine A(2A) receptor; Heteromerization; G protein-coupled receptors; Allosteric modulation; Cocaine
资金
- Swedish Research Council
- Spanish Ministry of Education and Science [SAF2005-00170, SAF2006-05481]
Adenosine A(2A) receptors (A(2A)Rs) and dopamine D-2 receptors (D(2)Rs) form constitutive heteromers in living cells and exhibit a strong functional antagonistic interaction. Recent findings give neurochemical evidence that extended cocaine self-administration in the rat give rise to an up-regulation of functional A(2A)Rs in the nucleus accumbens that return to baseline expression levels during cocaine withdrawal. In the present work, the acute in vitro effects of a concentration of cocaine known to fully block the dopamine (DA) transporter without exerting any toxic actions were investigated on A(2A)R and D2LR formed heteromers in transiently co-transfected HEK-293T cells. In vitro treatment of cocaine was found to produce changes in D2R homodimers and in A(2A)R-D2R heterodimers detected through bioluminescent energy transfer (BRET). Cocaine was found to produce a time- and concentration-dependent reduction in the BRETmax between A(2A)R-D2LR heterodimers and D2LR homodimers, but not A(2A)R homodimers, indicating its effect on D2R. Cocaine was evaluated with regard to D2R binding using a human D2LR stable expressing CHO cell line and was found to produce an increase in the affinity of hD(2L)R for DA. At the level of G protein-coupling, cocaine produced a small, but significant increase in DA-stimulated binding of GTP gamma S. However, cocaine failed to modulate D2R agonist-induced inhibition of cAMP in stable hD(2L)R CHO cells or the gating of GIRK channels in oocytes. Taken together, these results indicate a direct and specific effect of a moderate concentration of cocaine on the DA D2LR, that results in enhanced agonist recognition, G protein-coupling and an altered conformational state of D2R homodimers and A(2A)R-D2R heterodimers. (C) 2010 Elsevier Inc. All rights reserved.
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