The A_2A-receptor is a prototypical G_s-coupled receptors, which has several unusual features:In contrast to β-adrenergic receptors or rhodopsin, which engage their signalling cascade by collision coupling, the A_2A-receptor has long been known to couple to adenylyl cyclase by restricted collision coupling (1) and to form a tight complex with G_s (2). The structural basis for this is unknown, but the A_2A-receptor has an extended carboxyl terminus (122 amino acids after the conceptual end of the 7th transmembrane spanning β-helix TM7). The bulk of this extended C-terminus is essentially dispensable for G protein-coupling and is not required to support desensitization (3). However, it is the site of attachment of several additional proteins (4), namely α-actinin, intracellular portions of the D₂-dopamine receptor, ARNO, USP4 and translin-associated protein-X. Clearly, because of space constraints, it is not possible that all these proteins bind simultaneously and there must be rules that allow for the regulated interaction: association with the D₂-dopamine receptor is, for instance, thought to be stabilized by phosphorylation of a caseine kinase-I site in the C-terminus of the A_2A-receptor. The vast majority of group I (rhodopsin-like) G protein-coupled receptors carry one (or two) palmitoylated cysteine(s) within the proximal portion of their C-terminus (typically some 20 residues removed from the end of TM7). The palmitate thioester is thought to act as an additional anchor. This stabilizes the proximal segment in an α-helical conformation (referred to as helix 8 in the rhodopsin structure, which is oriented in a manner parallel to the membrane and perpendicular to helix 7). The A_2A-receptor does not have any cysteine residue in the proximal segment; there is only a single cysteine in position 394 in the human receptor and this is absent in other species orthologues (e.g. of rat and mouse). Thus one is tempted to speculate that the C-terminus of the A_2A-receptor is more flexible because it is not constrained by a lipid anchor. Finally, desensitization of the A_2A-adenosine receptor is contingent on the phosphorylation of a single threonine residue, T298 (3). This is remarkable, because efficient recruitment of arrestins typically requires a cluster of phosphates, which interact with the N-terminal phosphate sensor and thereby trigger the structural rearrangement that leads to the tight interaction between arrestin and receptor. We investigated the mode of coupling of the A_2A-receptor by visualizing agonist-induced changes in mobility of the YFP-tagged receptor by FRAP (= fluorescence recovery after photobleaching) microscopy. Agonist stimulation did not affect the mobility of the A_2A-receptor. In contrast (and as predicted from the model of receptor-mediated G protein activation), agonist challenge induced a decrease in the mobility of the D₂-receptor. When coexpressed in the same cell, the A_2A-receptor precluded the agonist-induced change in D₂-receptor mobility. Thus, the A_2A-receptor did not only undergo restricted collision coupling but it also restricted the mobility of the D₂-receptor. Restricted mobility was not due to tethering to the actin cytoskeleton and was not modulated by the presence of active or inactive ARNO, but was – in part – related to the cholesterol content of the membrane. Depletion of cholesterol increased receptor mobility, but blunted activation of adenylyl cyclase, which was accounted for by impaired formation of the ternary complex of agonist, receptor and G protein. These observations support the conclusion that the A_2A-receptor engages Gs and thus signals to adenylyl cyclase in cholesterol-rich domains of the membrane. The two distinct signalling pathways of the A_2A-receptor, cAMP accumulation and stimulation of MAP kinase (mitogen-activated protein kinase), were previously demonstrated to be independent of each other. Activation of MAP kinase is not contingent on G protein coupling. Accordingly, while disruption of cholesterol rich domains interfered with coupling to G_s, stimulation of MAP kinase by the A_2Areceptor was not impaired. These findings are consistent with a model where the recruitment of these two pathways occurs in spatially segregated microdomains of the plasma membrane. Thus, the A_2A-receptor is the first example of a G protein-coupled receptor documented to select signalling pathways in a manner dependent on the lipid microenvironment of the membrane.