Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer

被引：126

作者：

Bonaventura, Jordi ^{[1
,2
,3
,4
]}

Navarro, Gemma ^{[1
,2
,3
]}

Casado-Anguera, Veronica ^{[1
,2
,3
]}

Azdad, Karima ^{[5
]}

Rea, William ^{[4
]}

Moreno, Estefania ^{[1
,2
,3
]}

Brugarolas, Marc ^{[1
,2
,3
]}

Mallol, Josefa ^{[1
,2
,3
]}

Canela, Enric I. ^{[1
,2
,3
]}

Lluis, Carme ^{[1
,2
,3
]}

Cortes, Antoni ^{[1
,2
,3
]}

Volkow, Nora D. ^{[6
]}

Schiffmann, Serge N. ^{[5
]}

Ferre, Sergi ^{[4
]}

Casado, Vicent ^{[1
,2
,3
]}

机构：

[1] Univ Barcelona, Fac Biol, Dept Biochem & Mol Biol, E-08028 Barcelona, Spain

[2] Univ Barcelona, Ctr Invest Biomed Red Enfermedades Neurodegenerat, E-08028 Barcelona, Spain

[3] Univ Barcelona, Inst Biomed, E-08028 Barcelona, Spain

[4] NIDA, Integrat Neurobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA

[5] Univ Libre Bruxelles, Inst Neurosci, Neurophysiol Lab, B-1070 Brussels, Belgium

[6] NIAAA, NIH, Bethesda, MD 20892 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2015年 / 112卷 / 27期

关键词：

adenosine A(2A) receptor; dopamine D-2 receptor; caffeine; GPCR heteromers; HETEROMERS; CAFFEINE; DETERMINANTS; COMPLEXES; AFFINITY;

D O I：

10.1073/pnas.1507704112

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Adenosine A(2A) receptor (A(2A)R)-dopamine D-2 receptor (D2R) heteromers are key modulators of striatal neuronal function. It has been suggested that the psychostimulant effects of caffeine depend on its ability to block an allosteric modulation within the A(2A)R-D2R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D2R. We describe novel unsuspected allosteric mechanisms within the heteromer by which not only A(2A)R agonists, but also A(2A)R antagonists, decrease the affinity and intrinsic efficacy of D2R agonists and the affinity of D2R antagonists. Strikingly, these allosteric modulations disappear on agonist and antagonist coadministration. This can be explained by a model that considers A(2A)R-D2R heteromers as heterotetramers, constituted by A(2A)R and D2R homodimers, as demonstrated by experiments with bioluminescence resonance energy transfer and bimolecular fluorescence and bioluminescence complementation. As predicted by the model, high concentrations of A(2A)R antagonists behaved as A(2A)R agonists and decreased D2R function in the brain.

引用

页码：E3609 / E3618

页数：10

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