Adenosine receptor signaling in vitro and in vivo

This overview will focus on recent data from our laboratory. The four cloned human adenosine receptors stably transfected into Chinese hamster ovary cells were studied with respect to signaling via cyclic AMP and mitogen‐activated protein (MAP) kinases. Adenosine acted as a full agonist at all the adenosine receptors when increases (A 2A or A 2B receptors) or decreases (A 1 and A 3 receptors) in cyclic AMP accumulation were studied. Adenosine was approximately equipotent at A 1 , A 2A , and A 3 receptors, but approximately 50 times higher concentrations were needed at A 2B receptors. The potency of adenosine was such that levels encountered under basal physiological conditions (30–300 nM) were sufficient to activate all but the A 2B receptors. Inosine was a low‐efficacy agonist at A 1 and A 3 receptors but was inactive at A 2A and A 2B receptors. Thus, adenosine is the most important agonist and the only one at A 2A and A 2B receptors. When MAP kinase signaling was examined, adenosine was equipotent at all the four receptors, and significant activation was noted at 100 nM adenosine. The potency of adenosine is dependent not only on the type of receptor but also on receptor number. Thus, high potency of adenosine is seen only where the receptor is expressed abundantly. These and other results are reviewed and discussed in relation to agonist and antagonist effects in vivo. In particular, we summarize recent data that show that adenosine tonically activates A 2A receptors in the basal ganglia. Some aspects of the use of adenosine A 2A receptor antagonists in the treatment of Parkinson disease also are highlighted. Drug Dev. Res. 52:274–282, 2001. © 2001 Wiley‐Liss, Inc.