title: Constitutive formation of an RXFP1-signalosome: a novel paradigm in GPCR function and regulation.
abstract: The classical second messenger cAMP is important in diverse physiological processes, where its spatial and temporal compartmentalization allows precise control over multiple cellular events. Within this context, G-protein-coupled receptors (GPCRs) govern specialized pools of cAMP, which are functionally specific for the unique cellular effects attributed to a particular system. The relaxin receptor, RXFP1, is a GPCR that exerts pleiotropic physiological effects including a potent anti-fibrotic response, increased cancer metastases, and has efficacy as a vasodilator in heart failure. On a cellular level, relaxin stimulation of RXFP1 results in the activation of multiple G-protein pathways affecting cAMP accumulation. Specificity and diversity in the cAMP signal generated by RXFP1 is controlled by differential G-protein coupling dependent upon the background of cellular expression, and cAMP compartmentalization. Further complexity in cAMP signalling results from the constitutive assembly of an RXFP1-signalosome, which specifically responds to low concentrations of relaxin, and activates a distinct cAMP pathway. The RXFP1-signalosome is a higher-order protein complex that facilitates receptor sensitivity to attomolar concentration of peptide, exhibits constitutive activity and dual coupling to G-proteins and β-arrestins and reveals a concentration-biased agonism mediated by relaxin. The specific and directed formation of GPCR-centered signalosomes allows an even greater spatial and temporal control of cAMP, thus rationalizing the considerable physiological scope of this ubiquitous second messenger.
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge, UK.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Halls
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D018000:Receptors, Peptide / Q000502:physiology*; D015398:Signal Transduction; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D000071557:beta-Arrestins; C033395:relaxin receptors; D000242:Cyclic AMP