title: Constitutive activity in melanocortin-4 receptor: biased signaling of inverse agonists.
abstract: The melanocortin-4 receptor (MC4R) is a critical regulator of energy homeostasis, including both energy intake and energy expenditure. It mediates the actions of a number of hormones on energy balance. The endogenous ligands for MC4R include peptide agonists derived from processing of proopiomelanocortin and the antagonist Agouti-related peptide (AgRP). Wild-type MC4R has some basal (constitutive) activity. Naturally occurring and laboratory-generated mutations have been identified, which results in either increased or decreased basal activities. Impaired basal signaling has been suggested to be a cause of dysregulated energy homeostasis and early-onset obesity, although several constitutively active mutations have also been identified from obese patients. AgRP and several small-molecule antagonists have been shown to be inverse agonists in the Gs-cAMP pathway. However, in the extracellular signal-regulated kinase (ERK) 1/2 pathway, we showed that these inverse agonists are potent agonists, demonstrating convincingly that they are biased ligands. We also showed that some mutations that do not cause constitutive activation in the Gs-cAMP pathway cause constitutive activation in the ERK1/2 pathway, suggesting that they are biased receptors. The physiological and potential pathophysiological relevance of the biased constitutive signaling in MC4R and therapeutic potential remain to be investigated.
authors.affiliation: Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama, USA. Electronic address: taoyaxi@auburn.edu.
authors.forename: Ya-Xiong
authors.initials: YX
authors.lastname: Tao
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D054314:Drug Inverse Agonism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D006801:Humans; D009154:Mutation / Q000235:genetics*; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D044105:Receptor, Melanocortin, Type 4; D000242:Cyclic AMP; D048049:Extracellular Signal-Regulated MAP Kinases; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: Agouti-related peptide; Biased ligand; Biased receptor; Biased signaling; Constitutive activity; Inverse agonist; MAPK activation; Melanocortin-4 receptor; cAMP