Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 May 16;24(10):1892.
doi: 10.3390/molecules24101892.

Current Mechanistic and Pharmacodynamic Understanding of Melanocortin-4 Receptor Activation

Shubh Sharma  1 , Alastair S Garfield  2 , Bhavik Shah  3 , Patrick Kleyn  4 , Ilia Ichetovkin  5 , Ida Hatoum Moeller  6 , William R Mowrey  7 , Lex H T Van der Ploeg  8
Affiliations
Review

Current Mechanistic and Pharmacodynamic Understanding of Melanocortin-4 Receptor Activation

Shubh Sharma et al. Molecules. .

Abstract

In this work we summarize our understanding of melanocortin 4 receptor (MC4R) pathway activation, aiming to define a safe and effective therapeutic targeting strategy for the MC4R. Delineation of cellular MC4R pathways has provided evidence for distinct MC4R signaling events characterized by unique receptor activation kinetics. While these studies remain narrow in scope, and have largely been explored with peptidic agonists, the results provide a possible correlation between distinct ligand groups and differential MC4R activation kinetics. In addition, when a set of small-molecule and peptide MC4R agonists are compared, evidence of biased signaling has been reported. The results of such mechanistic studies are discussed.

Keywords: GαS signaling; cardiovascular profile; melanocortin-4 receptor; obesity; peptide agonist; receptor desensitization; receptor internalization.

PubMed Disclaimer

Conflict of interest statement

All authors are employees of Rhythm Pharmaceuticals.

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Marks D.L., Cone R.D. Central melanocortins and the regulation of weight during acute and chronic disease. Recent Prog. Horm. Res. 2001;56:359–375. doi: 10.1210/rp.56.1.359. - DOI - PubMed
    1. Cone R.D. The central melanocortin system and its role in energy homeostasis. Ann. Endocrinol. 1999;60:3–9. - PubMed
    1. Collet T.H., Dubern B., Mokrosinski J., Connors H., Keogh J.M., Mendes de Oliveira E., Henning E., Poitou-Bernert C., Oppert J.M., Tounian P., et al. Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency. Mol. Metab. 2017;6:1321–1329. doi: 10.1016/j.molmet.2017.06.015. - DOI - PMC - PubMed
    1. Clément K., Biebermann H., Farooqi I.S., Van der Ploeg L., Wolters B., Poitou C., Puder L., Fiedorek F., Gottesdiener K., Kleinau G., et al. MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency. Nat. Med. 2018;24:551–555. doi: 10.1038/s41591-018-0015-9. - DOI - PubMed
    1. Balthasar N., Coppari R., McMinn J., Shun M., Liu S.M., Charlotte E., Lee C.E., Tang V., Kenny C.D., McGovern R.A., et al. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron. 2004;42:983–991. doi: 10.1016/j.neuron.2004.06.004. - DOI - PubMed

MeSH terms

LinkOut - more resources