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.