Ghrelin receptor signaling in health and disease: a biased view

In a G-protein-coupled conformation, acyl-ghrelin occupies two cavities of the ghrelin receptor (GHSR1a) demarcated by an intertransmembrane (TMIII–TMVI) salt bridge, with its octanoyl group in one cavity and its N-terminal peptide moiety in the other. Only minor conformational differences exist between the ghrelin-bound, Gq-coupled GHSR1a and the Gi/o-coupled receptor.Agonist-stimulated GHSR1a activation rearranges the TMIII–TMVI salt bridge, produces intracellular outward movement of TMVI, extracellular inward movement of TMVII, and extracellular loop 2 (ECL2) capping of the orthosteric binding pocket. ECL2 is a key determinant of signaling and bias.GHSR1a adopts conformational states capable of dramatic Gq and β-arrestin signaling bias and pathway-dependent physiological effects. More evidence is needed to define β-arrestin-specific outcomes.Biased GHSR1a drugs can target chronic illness associated with metabolism- and age-related disease, including obesity, type 2 diabetes mellitus, cachexia, neurodegenerative disorders, and cardiovascular disease.