Abstract
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.