Received for publication May 17, 2006.
Revised May 17, 2006.
Accepted for publication May 17, 2006.

A tail of two signals: the C-terminus of the A_2A-adenosine receptor recruits alternative signaling pathways (Relates to article by Sun, et al. FastForward 14 April 2006)

Abstract

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 Gs-coupling. Originally the C-terminus was viewed mainly as the docking site for regulatory proteins of the -arrestin family. These -arrestins bind to residues which 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. 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. In spite of our ignorance about the precise mechanisms, the paper 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.

Key words: Adenosine, Purinergic, Gs family, Adenylyl cyclases, cAMP, GRKs, barrestins, Tumor suppressors

This article has been cited by other articles:

				C. Charalambous, I. Gsandtner, S. Keuerleber, L. Milan-Lobo, O. Kudlacek, M. Freissmuth, and J. Zezula Restricted Collision Coupling of the A2A Receptor Revisited: EVIDENCE FOR PHYSICAL SEPARATION OF TWO SIGNALING CASCADES J. Biol. Chem., April 4, 2008; 283(14): 9276 - 9288. [Abstract] [Full Text] [PDF]