Ghrelin receptor signaling in health and disease: a biased view.

As allosteric complexes, G-protein-coupled receptors (GPCRs) respond to extracellular stimuli and pleiotropically couple to intracellular transducers to elicit signaling pathway-dependent effects in a process known as biased signaling or functional selectivity. One such GPCR, the ghrelin receptor (GHSR_1a), has a crucial role in restoring and maintaining metabolic homeostasis during disrupted energy balance. Thus, pharmacological modulation of GHSR_1a bias could offer a promising strategy to treat several metabolism-based disorders. Here, we summarize current evidence supporting GHSR_1a functional selectivity in vivo and highlight recent structural data. We propose that precise determinations of GHSR_1a molecular pharmacology and pathway-specific physiological effects will enable discovery of GHSR_1a drugs with tailored signaling profiles, thereby providing safer and more effective treatments for metabolic diseases.