Functional and Neuroprotective Role of Striatal Adenosine A_2A Receptor Heterotetramers

In the striatum, adenosine A_2A receptors (A_2AR) are mainly expressed within the soma and dendrites of the striatopallidal neuron. A predominant proportion of these striatal postsynaptic A_2AR form part of the macromolecular complexes that include A_2AR-dopamine D₂ receptor (D₂R) heteromers, G_olf and G_i/o proteins, and the effector adenylyl cyclase (AC), subtype AC5. The A_2AR-D₂R heteromers have a tetrameric structure, constituted by A_2AR and D₂R homomers. By means of reciprocal antagonistic allosteric interactions and antagonistic interactions at the effector level between adenosine and dopamine, the A_2AR-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 A_2AR, which establish intermolecular interactions forming A₁R-A_2AR heterotetramers. Here, we review the functional role of both presynaptic and postsynaptic striatal A_2AR 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_2AR forming homomers or heteromers) are pathogenetically involved in neurological disorders, specifically in Parkinson's disease and restless legs syndrome.