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Review
, 153 Suppl 1 (Suppl 1), S184-90

The A(2A)-adenosine Receptor: A GPCR With Unique Features?

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Review

The A(2A)-adenosine Receptor: A GPCR With Unique Features?

J Zezula et al. Br J Pharmacol.

Abstract

The A(2A)-adenosine receptor is a prototypical G(s)-coupled receptor. However, the A(2A)-receptor has several structural and functional characteristics that make it unique. In contrast to the classical model of collision coupling described for the beta-adrenergic receptors, the A(2A)-receptor couples to adenylyl cyclase by restricted collision coupling and forms a tight complex with G(s). The mechanistic basis for this is not clear; restricted collision coupling may arise from the interaction of the receptor with additional proteins or due to the fact that G protein-coupling is confined to specialized membrane microdomains. The A(2A)-receptor has a long C-terminus (of >120 residues), which is for the most part dispensable for coupling to G(s). It was originally viewed as the docking site for kinases and the beta-arrestin family to initiate receptor desensitization and endocytosis. The A(2A)-receptor is, however, fairly resistant to agonist-induced internalization. Recently, the C-terminus has also been appreciated as a binding site for several additional 'accessory' proteins. Established interaction partners include alpha-actinin, ARNO, USP4 and translin-associated protein-X. In addition, the A(2A)-receptor has also been reported to form a heteromeric complex with the D(2)-dopamine receptor and the metabotropic glutamate receptor-5. It is clear that (i) this list cannot be exhaustive and (ii) that all these proteins cannot bind simultaneously to the receptor. There must be rules of engagement, which allow the receptor to elicit different biological responses, which depend on the cellular context and the nature of the concomitant signal(s). Thus, the receptor may function as a coincidence detector and a signal integrator.

Figures

Figure 1
Figure 1
Human embryonic kidney cells were transiently transfected with plasmids coding for the fluorescence-tagged versions of the A2A receptor and Rab5. Cells were then stimulated with the A2A-specific agonist CGS2168. Images were taken at the indicated times using a confocal laser microscope. For better visual distinction in the overlay, fluorescent A2A receptors were converted to red and Rab5 to green.
Figure 2
Figure 2
Schematic illustration of the signalling pathways of the A2A-adenosine receptor. The link between ARF6 and Ras remains to be elucidated.
Figure 3
Figure 3
Scheme of interaction sites on the C terminus of the A2A-adenosine receptor. Binding sites for α-actinin, ARNO, the D2 receptor and USP4 have been tentatively assigned in Burgueño et al. (2003), Gsandtner et al. (2005), Woods and Ferré (2005) and Milojevic et al. (2006), respectively. The orange circle identifies a threonine important for short-term desensitization (Palmer and Stiles, 1997). The red circle depicts the arginine unique to the A2A receptor. All other adenosine receptors have a cysteine in this position, which in most GPCRs is palmitoylated and thus stabilizes helix 8.

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