Molecular and Functional Characterization of Proteins Interacting with the C-Terminal Domains of 5-HT2 Receptors: Emergence of 5-HT2 “Receptosomes”

Many cellular functions are carried out by multiprotein complexes. The last five years of research have revealed that many G-protein coupled receptor (GPCR) functions that are not mediated by G proteins involve protein networks, which interact with their intracellular domains. This review focuses on one family of GPCRs activated by serotonin, the 5-HT2 receptor family, which comprises three closely related subtypes, the 5-HT2A, the 5-HT2B and the 5-HT2c receptors. These receptors still raise particular interest, because a large number of psychoactive drugs including hallucinogens, anti-psychotics, anxiolytics and anti-depressants, mediate their action, at least in part, through activation of 5-HT2 receptors. Recent studies based on two-hybrid screens, proteomic, biochemical and cell biology approaches, have shown that the C-terminal domains of 5-HT2 receptors interact with intracellular proteins. To date, the protein network associated with the C-terminus of the 5-HT2C receptor has been the most extensively characterized, using a proteomic approach combining affinity chromatography, mass spectrometry and immunoblotting. It includes scaffolding proteins containing one or several PDZ domains, signalling proteins and proteins of the cytoskeleton. Data indicating that the protein complexes interacting with 5-HT2 receptor C-termini tightly control receptor trafficking and receptor-mediated signalling will also be reviewed.