Adenosine A(2A) and A(3) Receptors Are Able to Interact with Each Other. A Further Piece in the Puzzle of Adenosine Receptor-Mediated Signaling

The aim of this paper was to check the possible interaction of two of the four purinergic P1 receptors, the A(2A) and the A(3). Discovery of the A(2A)–A(3) receptor complex was achieved by means of immunocytochemistry and of bioluminescence resonance energy transfer. The functional properties and heteromer print identification were addressed by combining binding and signaling assays. The physiological role of the novel heteromer is to provide a differential signaling depending on the pre-coupling to signal transduction components and/or on the concentration of the endogenous agonist. The main feature was that the heteromeric context led to a marked decrease of the signaling originating at A(3) receptors. Interestingly from a therapeutic point of view, A(2A) receptor antagonists overrode the blockade, thus allowing A(3) receptor-mediated signaling. The A(2A)–A(3) receptor heteromer print was detected in primary cortical neurons. These and previous results suggest that all four adenosine receptors may interact with each other. Therefore, each adenosine receptor could form heteromers with distinct properties, expanding the signaling outputs derived from the binding of adenosine to its cognate receptors.