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Perspective

A Tail of Two Signals: The C Terminus of the A_2A-Adenosine Receptor Recruits Alternative Signaling Pathways

Institute of Pharmacology, Center of Biomolecular Medicine and Pharmacology, Medical University of Vienna, Vienna, Austria

G protein-coupled receptors are endowed with carboxyl termini that vary greatly in length and sequence. In most instances, the distal portion of the C terminus is dispensable for G protein coupling. This is also true for the A_2A-adenosine receptor, where the last 100 amino acids are of very modest relevance to G_s coupling. The C terminus was originally viewed mainly as the docking site for regulatory proteins of the -arrestin family. These -arrestins bind to residues that have been phosphorylated by specialized kinases (G protein-coupled receptor kinases) and thereby initiate receptor desensitization and endocytosis. More recently, it has become clear that many additional "accessory" proteins bind to C termini of G protein-coupled receptors. The article by Sun et al. (p. 454) in the current issue of Molecular Pharmacology identifies translin-associated protein-X as yet another interaction partner of the A_2A receptor; translin-associated protein allows the A_2A receptor to impinge on the signaling mechanisms by which p53 regulates neuronal differentiation, but the underlying signaling pathways are uncharted territory. With a list of five known interaction partners, the C terminus of the A_2A receptor becomes a crowded place. Hence, there must be rules that regulate the interaction. This allows the C terminus to act as coincidence detector and as signal integrator. Despite our ignorance about the precise mechanisms, the article has exciting implications: the gene encoding for translin-associated protein-X maps to a locus implicated in some forms of schizophrenia; A_2A receptor agonists are candidate drugs for the treatment of schizophrenic symptoms. It is of obvious interest to explore a possible link.

Address correspondence to: Michael Freissmuth, Institute of Pharmacology, Medical University of Vienna, Währinger Str. 13a, A-1090 Vienna, Austria. E-mail: michael.freissmuth{at}meduniwien.ac.at

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Rescue of p53 Blockage by the A_2A Adenosine Receptor via a Novel Interacting Protein, Translin-Associated Protein X

Chung-Nan Sun, Hsiao-Chun Cheng, Jui-ling Chou, Shen-Yang Lee, Ya-Wen Lin, Hsing-Lin Lai, Hui-Mei Chen, and Yijuang Chern
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