TY - JOUR

T1 - The Complex Signaling Pathways of the Ghrelin Receptor

AU - Hedegaard, Morten Adler

AU - Holst, Birgitte

PY - 2020

Y1 - 2020

N2 - The ghrelin receptor (GhrR) is known for its strong orexigenic effects in pharmacological doses and has long been considered as a promising target for the treatment of obesity. Several antagonists have been developed to decrease the orexigenic signaling, but none of these have been approved for the treatment of obesity because of adverse effects and lack of efficacy. Heterodimerization and biased signaling are important concepts for G-protein coupled receptor (GPCR) signaling, and the influence of these aspects on the GhrR may be important for feeding behavior and obesity. GhrR has been described to heterodimerize with other GPCRs, such as the dopamine receptors 1 and 2, leading to a modulation of the signaling properties of both dimerization partners. Another complicating factor of GhrR-mediated signaling is its ability to activate several different signaling pathways on ligand stimulation. Importantly, some ligands have shown to be "biased" or "functionally selective," implying that the ligand favors a particular signaling pathway. These unique signaling properties could have a sizeable impact on the physiological functions of the GhrR system. Importantly, heterodimerization may explain why the GhrR is expressed in areas of the brain that are difficult for peptide ligands to access. One possibility is that the purpose of GhrR expression is to modulate the function of other receptors in addition to merely being independently activated. We suggest that a deeper understanding of the signaling properties of the GhrR will facilitate future drug discovery in the areas of obesity and weight management.

AB - The ghrelin receptor (GhrR) is known for its strong orexigenic effects in pharmacological doses and has long been considered as a promising target for the treatment of obesity. Several antagonists have been developed to decrease the orexigenic signaling, but none of these have been approved for the treatment of obesity because of adverse effects and lack of efficacy. Heterodimerization and biased signaling are important concepts for G-protein coupled receptor (GPCR) signaling, and the influence of these aspects on the GhrR may be important for feeding behavior and obesity. GhrR has been described to heterodimerize with other GPCRs, such as the dopamine receptors 1 and 2, leading to a modulation of the signaling properties of both dimerization partners. Another complicating factor of GhrR-mediated signaling is its ability to activate several different signaling pathways on ligand stimulation. Importantly, some ligands have shown to be "biased" or "functionally selective," implying that the ligand favors a particular signaling pathway. These unique signaling properties could have a sizeable impact on the physiological functions of the GhrR system. Importantly, heterodimerization may explain why the GhrR is expressed in areas of the brain that are difficult for peptide ligands to access. One possibility is that the purpose of GhrR expression is to modulate the function of other receptors in addition to merely being independently activated. We suggest that a deeper understanding of the signaling properties of the GhrR will facilitate future drug discovery in the areas of obesity and weight management.

KW - biased signaling

KW - heterodimerization

KW - ghrelin receptor

KW - G-protein coupled receptor

KW - MU-OPIOID RECEPTOR

KW - HORMONE SECRETAGOGUE RECEPTOR

KW - PROTEIN-COUPLED RECEPTORS

KW - CONSTITUTIVE ACTIVITY

KW - ACCESSORY PROTEIN

KW - FOOD-INTAKE

KW - BIASED LIGANDS

KW - DOUBLE-BLIND

KW - BODY-WEIGHT

KW - BETA-CELLS

U2 - 10.1210/endocr/bqaa020

DO - 10.1210/endocr/bqaa020

M3 - Review

C2 - 32049280

VL - 161

JO - Molecular Endocrinology

JF - Molecular Endocrinology

SN - 0888-8809

IS - 4

M1 - 020

ER -