Introduction

Adenosine is an endogenous nucleoside modulator released from almost all cells and is generated in the extracellular space by breakdown of ATP through a series of ectoenzymes, including the ENTDase (CD39) and 5'-nucleotidase (CD73 Linden, 2001). The latter dephosphorylates extracellular AMP into adenosine and constitutes a limiting step in its formation. Advances in Pharmacology, Volume 61 2011 Elsevier Inc. All rights reserved. 1054-3589 11 35.00 10.1016 B978-0-12-385526-8.00002-3...

T62

The A2AAR C-terminus has been defined as a crowded place where different accessory proteins may interact such as D2-dopamine receptors, a-actinin, ADP-ribosylation factor nucleotide site opener (ARNO), ubiquitin-specific protease (USP4), and translin-associated protein X (TRAX). The lack or the presence of such different partners may explain conflicting results deriving from A2AAR activation, for example, neuroprotection versus neurotoxicity (Sun et al., 2006a). A2aARs are found ubiquitously in...

Adenosine and the Regulation of Metabolism and Body Temperature

Adenosine levels are increased under conditions of energy deprivation, both because intracellular energy stores are reduced and because ATP is released. The adenosine thus formed can serve to influence energy homeosta-sis in a number of different ways, besides alterations in blood supply and cellular work (including contraction, maintenance of membrane potential, and biosynthesis), which will be covered in other chapters. Here, effects on energy homeostasis will be briefly reviewed. Adenosine...

Conclusion

With publication of the crystal structures of a handful of GPCRs with diffusible ligands, it is an exciting time for GPCR research. Given the unexpected binding orientation of the antagonist ZM241385 revealed by the A2A AR structure, the major impact of this structure was to illustrate that ligand selectivity across GPCRs is engendered not simply by differences in binding site residues or ligand structure but also by a variation in the topography of the ligand binding site. It also highlighted...

Info

I., Mileni, M., Chien, E. Y., Hanson, M. A., & Stevens, R. C. (2008). Microscale fluorescent thermal stability assay for membrane proteins. Structure, 16(3), 351-359. Altenbach, C., Kusnetzow, A. K., Ernst, O. P., Hofmann, K. P., & Hubbell, W. L. (2008). Highresolution distance mapping in rhodopsin reveals the pattern of helix movement due to activation. Proceedings of the National Academy of Sciences of the United States of America, 105(21), 7439-7444. Angel, T. E.,...

Primary Sequence and Covalent Modifications of the Adenosine A2A Receptors

The overall sequence similarity between human ARs is relatively high (Fig. 2). The adenosine A2a AR has higher sequence identity with the adeno-sine A2b AR (46 ) than with either the adenosine A1 AR (37 ) or A3 AR FIGURE 1 A summary of each class of GPCR crystal structure determined to date. (A) A2A AR T4 lysozyme receptor construct cocrystalized with the antagonist ZM241385. (B) Overhead view of the A2A AR crystal structure showing ZM241385 predominantly making interactions with helices 5,6,...

Vta

A. (1978). The control of the metabolism and the hormonal role of adenosine. Essays in Biochemistry, 14, 88-123. Astrup, A., & Toubro, S. (1993). Thermogenic, metabolic, and cardiovascular responses to ephedrine and caffeine in man. International Journal of Obesity, 17(Suppl. 1), S41-S43. Barraco, R. A., & Janusz, C. A. (1989). Respiratory effects of 5'-ethylcarboxamidoadenosine, an analog of adenosine, following microinjections into the nucleus tractus...

In Silico Screening

Until recently, ligand-based approaches to drug discovery were the only ones feasible for GPCRs. They have been and continue to be very successful, but, by definition, rely on a repertoire of already available chemical structures, generally derived from the structure of the endogenous ligand. Work from several research teams demonstrated the success of pharmacophore modeling for both the adenosine A1 AR and A2a AR in particular (Chang et al., 2004 Mantri et al., 2008 Moro et al., 2006 van Galen...