Functional and Neuroprotective Role of Striatal Adenosine A2AReceptor Heterotetramers

In the striatum, adenosine A 2A receptors (A 2A R) are mainly expressed within the soma and dendrites of the striatopallidal neuron. A predominant proportion of these striatal postsynaptic A 2A R form part of the macromolecular complexes that include A 2A R-dopamine D 2 receptor (D 2 R) heteromers, G olf and G i/o proteins, and the effector adenylyl cyclase (AC), subtype AC5. The A 2A R-D 2 R heteromers have a tetrameric structure, constituted by A 2A R and D 2 R homomers. By means of reciprocal antagonistic allosteric interactions and antagonistic interactions at the effector level between adenosine and dopamine, the A 2A R-D 2 R 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 A 1 receptors (A 1 R) and A 2A R, which establish intermolecular interactions forming A 1 R-A 2A R heterotetramers. Here, we review the functional role of both presynaptic and postsynaptic striatal A 2A R 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 A 2A R forming homomers or heteromers) are pathogenetically involved in neurological disorders, specifically in Parkinson's disease and restless legs syndrome.