Functional and Neuroprotective Role of Striatal Adenosine A2A Receptor Heterotetramers

IF 1.7 Q4 Pharmacology, Toxicology and Pharmaceutics
S. Ferré, F. Ciruela
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引用次数: 29

Abstract

In the striatum, adenosine A2A receptors (A2AR) are mainly expressed within the soma and dendrites of the striatopallidal neuron. A predominant proportion of these striatal postsynaptic A2AR form part of the macromolecular complexes that include A2AR-dopamine D2 receptor (D2R) heteromers, Golf and Gi/o proteins, and the effector adenylyl cyclase (AC), subtype AC5. The A2AR-D2R heteromers have a tetrameric structure, constituted by A2AR and D2R homomers. By means of reciprocal antagonistic allosteric interactions and antagonistic interactions at the effector level between adenosine and dopamine, the A2AR-D2R heterotetramer-AC5 complex acts an integrative molecular device, which determines a switch between the adenosine-facilitated activation and the dopamine-facilitated inhibition of the striatopallidal neuron. Striatal adenosine also plays an important presynaptic modulatory role, driving the function of corticostriatal terminals. This control is mediated by adenosine A1 receptors (A1R) and A2AR, which establish intermolecular interactions forming A1R-A2AR heterotetramers. Here, we review the functional role of both presynaptic and postsynaptic striatal A2AR heterotetramers as well as their possible neuroprotective role. We hypothesize that alterations in the homomer/heteromer stoichiometry (i.e., increase or decrease in the proportion of A2AR forming homomers or heteromers) are pathogenetically involved in neurological disorders, specifically in Parkinson's disease and restless legs syndrome.
纹状体腺苷A2A受体异四聚体的功能和神经保护作用
在纹状体中,腺苷A2A受体(A2AR)主要表达于纹状体状神经元的体细胞和树突内。这些纹状体突触后A2AR的主要比例形成了大分子复合物的一部分,包括A2AR-多巴胺D2受体(D2R)异构体、Golf和Gi/o蛋白,以及效应腺苷酸环化酶(AC), AC5亚型。A2AR-D2R异构体具有四聚体结构,由A2AR和D2R异构体组成。A2AR-D2R异四聚体- ac5复合体通过腺苷与多巴胺在效应水平上的拮抗变构相互作用和拮抗相互作用,作为一种整合的分子装置,决定了纹状体神经元在腺苷促进的激活和多巴胺促进的抑制之间的转换。纹状体腺苷也起着重要的突触前调节作用,驱动皮质纹状体末端的功能。这种控制是由腺苷A1受体(A1R)和A2AR介导的,它们建立分子间相互作用,形成A1R-A2AR异源四聚体。在这里,我们回顾了突触前和突触后纹状体A2AR异源四聚体的功能作用及其可能的神经保护作用。我们假设同种异构体化学计量的改变(即A2AR形成同种异构体或异构体比例的增加或减少)在病理上与神经系统疾病有关,特别是帕金森病和不宁腿综合征。
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