Adenosine Receptors

Introduction

           It has been recognized that the physiological effects of adenosine were mediated by specific membrane proteins, which were identified as members of G-protein- coupled receptor family and possess seven transmembrane helical regions. These receptors are known as the adenosine receptors (ARs). Currently, four AR subtypes have been cloned: A1AR, A2aAR, A2bAR, and A3AR. All subtypes are distinctly distributed throughout the body and adenosine receptor agonists and antagonists have potential therapeutic utility. Knowledge of AR amino acid structure has been utilized in mutagenesis studies to identify specific receptor regions that interact with distinct classes of ligands. Cloning of adensoine receptors has also permitted receptor regulatory processes such as desensitization to be studied in greater detail, in particular, the molecular mechanisms underlying this event. Cloning of the human A1AR has revealed that alternate splicing generates distinct receptor transcripts. The existence of a particular transcript in a tissue or cell apparently regulates the level of A1AR expression in the tissue.

         The receptors were classified as P1 and P2 purinergic receptors or purinoceptors depending on their preference for adenosine or adenosine nucleotides.

Characterization of Adenosine Receptor Subtypes

        Four distinct subtypes of adenosine receptors have been identified and termed as

A1 adenosine receptor

A2a  adenosine receptor

A2b  adenosine receptor

3A  adenosine receptor  `

        The A1 subclass of P1 receptor was originally defined on the basis of the ability of stable adenosine analogs to inhibit cAMP formation while the A2 receptor subclass was defined on the basis of the ability of adenosine analogs to increase cAMP formation (Londos et al., 1980: van Calker et al., 1979). Since it has become evident that there are multiple second messenger systems for adenosine (Morgan, 1991), the delineation of A1 and A2 receptors on the basis of the modulation of adenylyl cyclase activity has been replaced by pharmacological based classification (Hamprecht and van Calker, 1985). The A2 receptor has been further subdivided into A2a and A2b subclasses based on adenosine agonist affinity- A2a receptor has high affinity for a variety of agonists whileA2b has lower affinity for these same compounds-, anatomical distribution in the brain and limited pharmacological analysis (Bruns, 1980; Daly et al., 1983; Bruns and Pugsley, 1986). 

Receptor- Effector Coupling

As mentioned above, all the adenosine receptors are members of the superfamily of G protein coupled receptors. Much work has been undertaken to understand which G proteins the adenosine receptors couple to and which effector systems are modulated. It has became clear that many of these receptors are promiscuous in that they can interact with a variety of G proteins and effector systems such as adenylate cyclases and phospholipase C, leading to changes in intracellular calcium concentration, phosphorylation events and gene transcription. These interactions are summarized in the table. 

Table showing the receptor- effector coupling    

        The A1 receptors have been shown to interact with pertussis toxin- sensitive G proteins, particularly G_i1,2,3 and G_o in reconstituted systems (Freissmuth et al., 1991). However, whether these interactions all occur in vivo remains largely unknown. Studies on the regulation of A1ARs have documented that activation of the A1ARs can indeed modulate the levels of G_ia1 and G_ia2. Whether these modulations are the direct result of the receptor interacting with these  proteins, or whether the A1 receptor can act through the G_q- like proteins in a pertussis toxin- insensitive manner. The A1ARs have been documented to interact with at least three effector systems, namely adenylyl cyclase, phospholipase C and potassium channels (Palmer and Stiles, 1995; Olah and Stiles, 1995)

          The A2a receptor is known to interact with the G_s protein, which mediates activation of adenylyl cylase. The A2b receptor has been documented to interact with  the Gs protein, in which case it can either increase adenylyl cyclase activity or open calcium channels. Finally, the A3AR has been documented to interact with and activate both and activate both G_ia2 and G_ia3, but whether is is able to interact with other G protein remains to be determined (Palmer et al., 1995). This receptor predominately interacts in a inhibitory manner with adenylyl cyclase and in a stimulatory manner phospholipase C. This interaction appears to be pertussis toxin- sensitive, suggesting that it is interacting through the G_i- like proteins rather than the G_q- type proteins.

Citations

1. Morgan, P. F. (1991) Post- receptor mechanisms. In Adenosine and the Nervous System, Stone, T. W., Ed., Academic press, London, pp. 119- 136.

2. Hamprecht, B. and van Calker, D. (1985) Nomenclature of adenosine receptors. Trends Pharmacol. Sci. 6, 153- 154.