PT - JOURNAL ARTICLE AU - Ingrid Gsandtner AU - Michael Freissmuth TI - A Tail of Two Signals: The C Terminus of the A<sub>2A</sub>-Adenosine Receptor Recruits Alternative Signaling Pathways AID - 10.1124/mol.106.026757 DP - 2006 Aug 01 TA - Molecular Pharmacology PG - 447--449 VI - 70 IP - 2 4099 - http://molpharm.aspetjournals.org/content/70/2/447.short 4100 - http://molpharm.aspetjournals.org/content/70/2/447.full SO - Mol Pharmacol2006 Aug 01; 70 AB - 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 A2A-adenosine receptor, where the last 100 amino acids are of very modest relevance to Gs coupling. The C terminus was originally viewed mainly as the docking site for regulatory proteins of the β-arrestin family. These β-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 A2A receptor; translin-associated protein allows the A2A 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 A2A 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; A2A receptor agonists are candidate drugs for the treatment of schizophrenic symptoms. It is of obvious interest to explore a possible link.