The role of receptor structure in determining adenosine receptor activity

Adenosine produces a wide variety of physiological effects through the acti vation of cell surface adenosine receptors (ARs). ARs are members of the G- protein-coupled receptor family, and currently, four subtypes, the A(1)AR, A(2A)AR, A(2B)AR, and A(3)AR, are recognized. This review focuses on the ro le of receptor structure in governing various facets of AR activity. Ligand -binding properties of ARs are primarily dictated by amino acids in the tra nsmembrane domains of the receptors, although a role for extracellular doma ins of certain ARs has been suggested. Studies have identified certain amin o acids conserved amongst AR subtypes that are critical for ligand recognit ion, as well as additional residues that may differentiate between agonist and antagonist ligands. Receptor regions responsible for activation of G(s) have been identified for the A(2A)AR. The location of these intracellular sites is consistent with findings described for other G-protein-coupled rec eptors. Site-directed mutagenesis has been employed to analyze the structur al basis for the differences in the kinetics of the desensitization respons e displayed by various AR subtypes. For the A(2A)AR and A(3)AR, agonist-sti mulated phosphorylation of the AR, presumably via a G-protein receptor kina se, has been shown to occur. For these AR subtypes, intracellular regions o r individual amino acids that may be targets for this phosphorylation have been identified. Finally, the role of A(1)AR gene structure in regulating t he expression of this AR subtype is reviewed. (C) 2000 Elsevier Science Inc All rights reserved.