Adrenergic Ligands-Induced Transinhibition of EGFR by GPR27 and GPR173 Reveals a Novel GPCR Signaling Mechanism

G protein-coupled receptors 27 and 173 (GPR27 and GPR173) are part of the "Super Conserved Receptors Expressed in Brain" (SREB) family, alongside GPR85. While the endogenous ligands and functions of SREB receptors are still unknown, GPR27 has been implicated in insulin secretion and tumorigenesis, whereas GPR173 has been proposed to be a receptor mediating biological effects of phoenixin-20 amide. Here, we show that substituting GPR27’s C-terminal domain with that of the β1 adrenergic receptor (β1AR) yields a chimera with β1AR-like ligand selectivity and cellular functions. Interestingly, stimulation of GPR27 with isoproterenol and adrenergic ligands inhibited epidermal growth factor (EGF)-induced serum-responsive element (SRE) activation, independently of G proteins and β-arrestins, and induced GPR27 internalization.Surprisingly, GPR173 responded exclusively to noradrenaline, showing both inhibition of EGF-induced SRE activity and receptor internalisation, whereas GPR85 remained unresponsive to the tested adrenergic ligands. Taken together, these intriguing findings suggest that GPR27 and GPR173 respond to adrenergic ligands to transinhibit EGFR through a unique and atypical signaling mechanism, previously undescribed for any known GPCR. Moreover, we provide the first evidence of ligand-induced functional transinhibition of a receptor tyrosine kinase, such as EGFR, by a GPCR, opening new research lines with translational potential.