Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers
Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers
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DOI：
10.1523/jneurosci.3574-05.2006
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发表时间：
2006-02-15
影响因子：
5.3
通讯作者：
Franco, R
中科院分区：
文献类型：
--
作者：
Ciruela, F;Casadó, V;Franco, R
G蛋白偶联受体的异聚体的功能作用是一个有争议的问题。在本研究中，我们证明了腺苷A（1）受体（A（1）Rs）和A（2A）受体（A（2A）Rs）的异聚化允许腺苷对多巴胺能神经传递进行微调调节。通过免疫共沉淀、生物发光和时间分辨荧光共振能量转移技术，我们证实了共转染细胞表面存在A（1）R-A（2A）R异聚体。免疫胶体金检测和免疫共沉淀实验表明，A（1）R和A（2A）R共定位于同一个纹状体内的多巴胺能神经末梢。在共转染细胞和大鼠纹状体中的放射性配体结合实验表明，A（1）R-A（2A）R异聚体的主要生化特征是A（2A）R活化降低A（1）R对激动剂的亲和力的能力。这提供了一种开关机制，通过该机制，低浓度和高浓度的腺苷分别抑制和刺激谷氨酸释放。此外，还表明A（1）R-A（2A）R异聚体构成咖啡因的独特靶标，并且慢性咖啡因治疗导致A（1）R-A（2A）R异聚体功能的改变，这可能是对咖啡因的精神作用的强耐受性的基础。
The functional role of heteromers of G-protein-coupled receptors is a matter of debate. In the present study, we demonstrate that heteromerization of adenosine A(1) receptors (A(1)Rs) and A(2A) receptors (A(2A)Rs) allows adenosine to exert a fine-tuning modulation of glutamatergic neurotransmission. By means of coimmunoprecipitation, bioluminescence and time-resolved fluorescence resonance energy transfer techniques, we showed the existence of A(1)R-A(2A)R heteromers in the cell surface of cotransfected cells. Immunogold detection and coimmunoprecipitation experiments indicated that A(1)R and A(2A)R are colocalized in the same striatal glutamatergic nerve terminals. Radioligand-binding experiments in cotransfected cells and rat striatum showed that a main biochemical characteristic of the A(1)R-A(2A)R heteromer is the ability of A(2A)R activation to reduce the affinity of the A(1)R for agonists. This provides a switch mechanism by which low and high concentrations of adenosine inhibit and stimulate, respectively, glutamate release. Furthermore, it is also shown that A(1)R-A(2A)R heteromers constitute a unique target for caffeine and that chronic caffeine treatment leads to modifications in the function of the A(1)R-A(2A)R heteromer that could underlie the strong tolerance to the psychomotor effects of caffeine.