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Constitutive activity in melanocortin-4 receptor: biased signaling of inverse agonists
1Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama, USA.
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.
Insights
The melanocortin-4 receptor (MC4R) regulates energy balance. Some MC4R drugs act differently in distinct signaling pathways, acting as agonists in one and inverse agonists in another, impacting obesity research.
Area of Science:
- Biochemistry
- Molecular Biology
- Endocrinology
Background:
- The melanocortin-4 receptor (MC4R) is a key regulator of energy homeostasis, influencing appetite and metabolism.
- MC4R activity is modulated by hormones and ligands like Agouti-related peptide (AgRP).
- Mutations in MC4R can lead to altered basal activity, potentially causing obesity.
Purpose of the Study:
- To investigate the signaling bias of MC4R ligands and mutations.
- To explore the differential activation of MC4R in the Gs-cAMP and ERK1/2 pathways.
- To understand the implications of biased signaling in energy balance and obesity.
Main Methods:
- Assessed the activity of AgRP and small-molecule antagonists in Gs-cAMP and ERK1/2 signaling pathways.
- Investigated MC4R mutations for constitutive activation in different signaling pathways.
- Utilized biochemical assays to measure receptor activity.
Main Results:
- AgRP and antagonists act as inverse agonists in the Gs-cAMP pathway but as agonists in the ERK1/2 pathway, demonstrating biased agonism.
- Certain MC4R mutations cause constitutive activation in the ERK1/2 pathway without affecting the Gs-cAMP pathway, indicating biased receptors.
- These findings reveal a novel mechanism of MC4R regulation.
Conclusions:
- MC4R ligands and mutations can exhibit biased signaling, differentially activating downstream pathways.
- Biased signaling in MC4R may contribute to energy homeostasis dysregulation and obesity.
- Further research is needed to elucidate the physiological relevance and therapeutic potential of biased MC4R signaling.
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