Adenosine receptors: G protein-mediated signalling and the role of accessory proteins

Ever since the discovery of the effects of adenosine in the circulation, adenosine receptors continue to represent a promising drug target. Firstly, this is due to the fact that the receptors are expressed in a large variety of cells; in particular, the actions of adenosine (or, respectively, of the antagonistic methylxanthines) in the central nervous system, in the circulation, on immune cells and on other tissues can be beneficial in certain disorders. Secondly, there exists a large number of ligands, which have been generated by introducing several modifications in the structure of the lead compounds (adenosine and methylxanthine), some of them highly specific. Four adenosine receptor subtypes have been identified by molecular cloning; they belong to the family of G protein-coupled receptors, which transfer signals by activating heterotrimeric G proteins. It has been appreciated recently that accessory proteins impinge on the receptor/G protein interaction and thus modulate the signalling reaction. These accessory components may be thought as adaptors that redirect the signalling pathway to elicit a cell-specific response. Here, we review the recent literature on adenosine receptors and place a focus on the role of accessory proteins in the organisation of adenosine receptor signalling. These components have been involved in receptor sorting, in the control of signal amplification and in the temporal regulation of receptor activity, while the existence of others is postulated on the basis of atypical cellular reactions elicited by receptor activation.