Melanocortin

Last updated
proopiomelanocortin derivatives
POMC
   
γ-MSH ACTH β-lipotropin
     
  α-MSH CLIP γ-lipotropin β-endorphin
    
   β-MSH  

The melanocortins are a family of neuropeptide hormones which are the ligands of the melanocortin receptors [1] The melanocortin system consists of melanocortin receptors, ligands, and accessory proteins. The genes of the melanocortin system are found in chordates. [2] Melanocortins were originally named so because their earliest known function was in melanogenesis. It is now known that the melanocortin system regulates diverse functions throughout the body, including inflammatory response, fibrosis, melanogenesis, steroidogenesis, energy homeostasis, sexual function, and exocrine gland function. [3] [4] [1]

Contents

There are four endogenous melanocortin agonists which are derived from post-transcriptional processing of the precursor molecule proopiomelanocortin (POMC) (Figure 1). [5] They are Adrenocorticotropic hormone (ACTH), a-melanocyte stimulating hormone (MSH), b-MSH, and g-MSH. In addition to agonists which activate melanocortin receptors , there are two antagonists which inhibit receptor activity, Agouti and Agouti-related protein (Agrp). Lastly, the ligand β-defensin 3 acts as a neutral melanocortin receptor antagonist. [6]

Receptors

The 5 melanocortin receptors are seven-transmembrane G-protein coupled receptors with differing ligand affinities, tissue and cell type expression, and downstream functions (Figure 2). [7] MC1R is expressed on melanocytes, macrophages, epithelial cells, endothelial cells, fibroblasts, monocytes and numerous other immune cells, but is also present in brain, testis, and intestine. [8] Its main functions are in melanogenesis and anti-inflammatory signaling. [9] MC2R is expressed in the adrenal cortex and adipocytes and promotes steroidogenesis. [10] MC3R and MC4R are primarily expressed in the brain and regulate energy homeostasis. [1] MC3R is additionally involved in immunomodulation while MC4R has a role in sexual function. [11] [12] MC5R is highly expressed in skin and adrenal glands and has a role in exocrine function. [13] MC2R is activated exclusively by ACTH, whereas the other 4 receptors can be activated by ACTH, a-MSH, b-MSH, and g-MSH, although the binding affinities differ. For all the melanocortin receptors, binding of an agonistic ligand activates the receptor, leading to dissociation of the G protein and activation of the enzyme adenyl cyclase. Adenyl cyclase then cleaves ATP to generate the second messenger cyclic AMP (cAMP), which in turn activates multiple downstream pathways.  

There are two known accessory proteins belonging to the melanocortin system which modulate function of the receptors. These are melanocortin-2-receptor accessory protein (MRAP) and MRAP2. [14]

Therapeutic Uses

FDA-approved

In 2019 the FDA approved the first drug targeting melanocortin receptors, Vyleesi (Bremelanotide) which was developed by Palatin Technologies, Inc.  The Melanocortin system has been largely unexplored in drug development but recent approvals, its novelty and wide-spread application across indications has led it to the frontier of new discoveries in medicine. Since Vyleesi approval  multiple companies have initiated drug discovery programs targeting the melanocortin system. Bremelanotide (Vyleesi) is approved for treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. [15] At therapeutic dose levels, it activates MC1R and MC4R. [16]

Setmelanotide (Imcivree) is an MC4R agonist approved for chronic weight management in patients with genetic obesity. [17] [18]

Afamelanotide (Scenesse) is an MC1R agonist approved for patients with erythropoietic protoporphyria to increase pain-free light exposure. [19]

Clinical trials

PL9643, an ophthalmic solution, is being tested in phase 3 clinical trials to determine safety and efficacy in patients with dry eye. [20] PL9643 activates MC1R, MC3R, MC4R and MC5R. Completed Phase 2 studies demonstrated positive results for the treatment of dry eye disease. [21]

Dersimelagon (MT-7117) is an orally administered MC1R agonist being tested in phase 3 clinical trials to evaluate safety and tolerability in patients with erythropoietic protoporphyria or X-linked protoporphyria. [22]

Resomelagon (AP1189) is an orally administered MC1R and MC3R agonist being tested in three phase 2 clinical trials to study safety and efficacy in patients with rheumatoid arthritis and idiopathic membranous nephropathy. [23] [24] [25]

Function

The melanocortin system is one of the mammalian body's tools to regulate food intake in a push-pull fashion. [26] The only neurons known to release melanocortins are located in the arcuate nucleus of the hypothalamus. However, melanocortins are also produced by keratinocytes in response to UV exposure. Accordingly, there is a subpopulation called POMC neurons and one called AgRP neurons. [27] When POMC neurons release α-MSH, appetite is decreased. On the other hand, when AgRP neurons release AgRP, appetite is stimulated.

Leptin, the energy surfeit hormone, and Ghrelin, the hunger hormone, are upstream regulators of the melanocortin system in the brain. [27] These hormones also regulate the release of peptides other than the melanocortins. Disturbance of the leptin-melanocortin pathway can lead to early onset obesity as well as various metabolic disorders and suppressed immune function. [28]

Related Research Articles

<span class="mw-page-title-main">Adrenocorticotropic hormone</span> Pituitary hormone

Adrenocorticotropic hormone is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological stress. Its principal effects are increased production and release of cortisol and androgens by the cortex and medulla of the adrenal gland, respectively. ACTH is also related to the circadian rhythm in many organisms.

<span class="mw-page-title-main">Proopiomelanocortin</span> Mammalian protein found in Homo sapiens

Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior pituitary from the 267-amino-acid-long polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the removal of a 26-amino-acid-long signal peptide sequence during translation. POMC is part of the central melanocortin system.

The melanocyte-stimulating hormones, known collectively as MSH, also known as melanotropins or intermedins, are a family of peptide hormones and neuropeptides consisting of α-melanocyte-stimulating hormone (α-MSH), β-melanocyte-stimulating hormone (β-MSH), and γ-melanocyte-stimulating hormone (γ-MSH) that are produced by cells in the pars intermedia of the anterior lobe of the pituitary gland.

<span class="mw-page-title-main">Arcuate nucleus</span>

The arcuate nucleus of the hypothalamus is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several important and diverse populations of neurons that help mediate different neuroendocrine and physiological functions, including neuroendocrine neurons, centrally projecting neurons, and astrocytes. The populations of neurons found in the arcuate nucleus are based on the hormones they secrete or interact with and are responsible for hypothalamic function, such as regulating hormones released from the pituitary gland or secreting their own hormones. Neurons in this region are also responsible for integrating information and providing inputs to other nuclei in the hypothalamus or inputs to areas outside this region of the brain. These neurons, generated from the ventral part of the periventricular epithelium during embryonic development, locate dorsally in the hypothalamus, becoming part of the ventromedial hypothalamic region. The function of the arcuate nucleus relies on its diversity of neurons, but its central role is involved in homeostasis. The arcuate nucleus provides many physiological roles involved in feeding, metabolism, fertility, and cardiovascular regulation.

<span class="mw-page-title-main">Bremelanotide</span> Chemical compound

Bremelanotide, sold under the brand name Vyleesi, is a medication used to treat low sexual desire in women. Specifically it is used for low sexual desire which occurs before menopause and is not due to medical problems, psychiatric problems, or problems within the relationship. It is given by an injection just under the skin of the thigh or abdomen.

<span class="mw-page-title-main">Agouti-related peptide</span> Mammalian protein found in Homo sapiens

Agouti-related protein (AgRP), also called agouti-related peptide, is a neuropeptide produced in the brain by the AgRP/NPY neuron. It is synthesized in neuropeptide Y (NPY)-containing cell bodies located in the ventromedial part of the arcuate nucleus in the hypothalamus. AgRP is co-expressed with NPY and acts to increase appetite and decrease metabolism and energy expenditure. It is one of the most potent and long-lasting of appetite stimulators. In humans, the agouti-related peptide is encoded by the AGRP gene.

Melanocortin receptors are members of the rhodopsin family of 7-transmembrane G protein-coupled receptors.

<span class="mw-page-title-main">Flibanserin</span> Medication

Flibanserin, sold under the brand name Addyi, is a medication approved for the treatment of pre-menopausal women with hypoactive sexual desire disorder (HSDD). The medication improves sexual desire, increases the number of satisfying sexual events, and decreases the distress associated with low sexual desire. The most common side effects are dizziness, sleepiness, nausea, difficulty falling asleep or staying asleep and dry mouth.

<span class="mw-page-title-main">ACTH receptor</span> Mammalian protein found in Homo sapiens

The adrenocorticotropic hormone receptor or ACTH receptor also known as the melanocortin receptor 2 or MC2 receptor is a type of melanocortin receptor (type 2) which is specific for ACTH. A G protein–coupled receptor located on the external cell plasma membrane, it is coupled to Gαs and upregulates levels of cAMP by activating adenylyl cyclase. The ACTH receptor plays a role in immune function and glucose metabolism.

<span class="mw-page-title-main">Melanocortin 4 receptor</span> Mammalian protein found in Homo sapiens

Melanocortin 4 receptor (MC4R) is a melanocortin receptor that in humans is encoded by the MC4R gene. It encodes the MC4R protein, a G protein-coupled receptor (GPCR) that binds α-melanocyte stimulating hormone (α-MSH). In mouse models, MC4 receptors have been found to be involved in feeding behaviour, the regulation of metabolism, sexual behaviour, and male erectile function.

<span class="mw-page-title-main">Melanocortin 3 receptor</span> Mammalian protein found in Homo sapiens

Melanocortin 3 receptor (MC3R) is a protein that in humans is encoded by the MC3R gene.

The central melanocortin system is defined anatomically as a collection of central nervous system circuits which include:

<span class="mw-page-title-main">Afamelanotide</span> Chemical compound

Afamelanotide, sold under the brand name Scenesse, is a synthetic peptide and analogue of α-melanocyte stimulating hormone. It has been used to prevent skin damage from the sun in people with erythropoietic protoporphyria in the European Union since January 2015 and the United States since October 2019. As a medication, it is administered in subcutaneous implant form. Each implant lasts two months.

<span class="mw-page-title-main">Deslorelin</span> Chemical compound

Deslorelin, sold under the brand names Ovuplant, SucroMate, and Suprelorin among others, is an injectable gonadotropin releasing hormone superagonist which is used in veterinary medicine for various indications.

<span class="mw-page-title-main">Melanocortin 1 receptor</span> G protein–coupled receptor

The melanocortin 1 receptor (MC1R), also known as melanocyte-stimulating hormone receptor (MSHR), melanin-activating peptide receptor, or melanotropin receptor, is a G protein–coupled receptor that binds to a class of pituitary peptide hormones known as the melanocortins, which include adrenocorticotropic hormone (ACTH) and the different forms of melanocyte-stimulating hormone (MSH). It is coupled to Gαs and upregulates levels of cAMP by activating adenylyl cyclase in cells expressing this receptor. It is normally expressed in skin and melanocytes, and to a lesser degree in periaqueductal gray matter, astrocytes and leukocytes. In skin cancer, MC1R is highly expressed in melanomas but not carcinomas.

α-Melanocyte-stimulating hormone (α-MSH) is an endogenous peptide hormone and neuropeptide of the melanocortin family, with a tridecapeptide structure and the amino acid sequence Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2. It is the most important of the melanocyte-stimulating hormones (MSHs) (also known as melanotropins) in stimulating melanogenesis, a process that in mammals (including humans) is responsible for pigmentation primarily of the hair and skin. It also plays a role in feeding behavior, energy homeostasis, sexual activity, and protection against ischemia and reperfusion injury.

<span class="mw-page-title-main">Setmelanotide</span> Chemical compound

Setmelanotide, sold under the brand name Imcivree, is a medication used for the treatment of genetic obesity caused by a rare single-gene mutation.

<i>beta</i>-Melanocyte-stimulating hormone Chemical compound

β-Melanocyte-stimulating hormone (β-MSH) is an endogenous peptide hormone and neuropeptide. It is a melanocortin, specifically, one of the three types of melanocyte-stimulating hormone (MSH), and is produced from proopiomelanocortin (POMC). It is an agonist of the MC1, MC3, MC4, and MC5 receptors.

γ-Melanocyte-stimulating hormone (γ-MSH) is an endogenous peptide hormone and neuropeptide. It is a melanocortin, specifically, one of the three types of melanocyte-stimulating hormone (MSH), and is produced from proopiomelanocortin (POMC). It is an agonist of the MC1, MC3, MC4, and MC5 receptors. It exists in three forms, γ1-MSH, γ2-MSH, and γ3-MSH.

Drugs and sexual desire is about sexual desire being manipulated through drugs from various approaches. Sexual desire is generated under the effects from sex hormones and microcircuits from brain regions. Neurotransmitters play essential roles in stimulating and inhibiting the processes that lead to libido production in both men and women. For instance, a positive stimulation is modulated by dopamine from the medial preoptic area in the hypothalamus and norepinephrine. At the same time, inhibition occurs when prolactin and serotonin are released for action.

References

  1. 1 2 3 Ericson, M.D., et al., Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016. Biochim Biophys Acta Mol Basis Dis, 2017. 1863(10 Pt A): p. 2414-2435.
  2. ↑ Cortes, R., et al., Evolution of the melanocortin system. Gen Comp Endocrinol, 2014. 209: p. 3-10.
  3. ↑ Chen, W., et al., Exocrine gland dysfunction in MC5-R-deficient mice: evidence for coordinated regulation of exocrine gland function by melanocortin peptides. Cell, 1997. 91(6): p. 789-98.
  4. ↑ Wang, W., et al., Melanocortin Regulation of Inflammation. Front Endocrinol (Lausanne), 2019. 10: p. 683.
  5. ↑ Arnason, B.G., et al., Mechanisms of action of adrenocorticotropic hormone and other melanocortins relevant to the clinical management of patients with multiple sclerosis. Mult Scler, 2013. 19(2): p. 130-6.
  6. ↑ Nix, M.A., et al., Molecular and functional analysis of human beta-defensin 3 action at melanocortin receptors. Chem Biol, 2013. 20(6): p. 784-95.
  7. ↑ Butler, A.A., et al., A Life without Hunger: The Ups (and Downs) to Modulating Melanocortin-3 Receptor Signaling. Front Neurosci, 2017. 11: p. 128.
  8. ↑ Salazar-Onfray, F., et al., Tissue distribution and differential expression of melanocortin 1 receptor, a malignant melanoma marker. Br J Cancer, 2002. 87(4): p. 414-22.
  9. ↑ Wolf Horrell, E.M., M.C. Boulanger, and J.A. D'Orazio, Melanocortin 1 Receptor: Structure, Function, and Regulation. Front Genet, 2016. 7: p. 95.
  10. ↑ Fridmanis, D., A. Roga, and J. Klovins, ACTH Receptor (MC2R) Specificity: What Do We Know About Underlying Molecular Mechanisms? Front Endocrinol (Lausanne), 2017. 8: p. 13.
  11. ↑ Catania, A., et al., Targeting melanocortin receptors as a novel strategy to control inflammation. Pharmacol Rev, 2004. 56(1): p. 1-29.
  12. ↑ Martin, W.J. and D.E. MacIntyre, Melanocortin receptors and erectile function. Eur Urol, 2004. 45(6): p. 706-13.
  13. ↑ Hatta, N., et al., Expression, candidate gene, and population studies of the melanocortin 5 receptor. J Invest Dermatol, 2001. 116(4): p. 564-70.
  14. ↑ Chan, L.F., et al., MRAP and MRAP2 are bidirectional regulators of the melanocortin receptor family. Proc Natl Acad Sci U S A, 2009. 106(15): p. 6146-51.
  15. ↑ Administration, U.F.a.D. FDA approves new treatment for hypoactive sexual desire disorder in premenopausal women. 2019; Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-hypoactive-sexual-desire-disorder-premenopausal-women#:~:text=FDA%20approves%20new%20treatment%20for%20hypoactive%20sexual%20desire%20disorder%20in%20premenopausal%20women,-Share&text=The%20U.S.%20Food%20and%20Drug,(HSDD)%20in%20premenopausal%20women.
  16. ↑ Administration, U.F.a.D. Vyleesi prescribing information. 2019; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210557s000lbl.pdf.
  17. ↑ Administration, U.F.a.D. FDA approves first treatment for weight management for people with certain rare genetic conditions. 2020; Available from: https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-weight-management-people-certain-rare-genetic-conditions#:~:text=%5B11%2F27%2F2020%5D,POMC)%20deficiency%2C%20proprotein%20subtilisin%2F.
  18. ↑ Markham, A., Setmelanotide: First Approval. Drugs, 2021. 81(3): p. 397-403.
  19. ↑ Administration, U.F.a.D. FDA approves first treatment to increase pain-free light exposure in patients with a rare disorder. 2019; Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-increase-pain-free-light-exposure-patients-rare-disorder.
  20. ↑ Administration, U.F.a.D. A Phase 3, Multi-Center Study Evaluating PL9643 in Patients With Dry Eye (MELODY-1). 2022; Available from: https://clinicaltrials.gov/ct2/show/NCT05201170?term=palatin&draw=2&rank=1.
  21. ↑ Administration, U.F.a.D. Efficacy and Safety of PL9643 Ophthalmic Solution in Subjects With Dry Eye. 2020; Available from: https://clinicaltrials.gov/ct2/show/NCT04268069?term=palatin&draw=2&rank=9.
  22. ↑ Administration, U.F.a.D. Extension Study to Evaluate Safety and Tolerability of Oral Dersimelagon (MT-7117) in Subjects With Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP). 2021; Available from: https://clinicaltrials.gov/ct2/show/NCT05005975?term=mt-7117&draw=2&rank=9.
  23. ↑ Administration, U.F.a.D. A Study of the Safety, Tolerability, Pharmacokinetics and Efficacy of Treatment With AP1189 in Patients With iMN. 2020; Available from: https://clinicaltrials.gov/ct2/show/NCT04456816?term=ap1189&draw=2&rank=2.
  24. ↑ Administration, U.F.a.D. A Safety & Efficacy Study of Treatment With AP1189 in Rheumatoid Arthritis Patients naïve to DMARD Treatment (EXPAND); Available from: https://clinicaltrials.gov/ct2/show/NCT05516979
  25. ↑ Administration, U.F.a.D. A Dose-range Study of the Safety and Efficacy of Treatment in Adult Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate (RESOLVE); Available from: https://clinicaltrials.gov/ct2/show/NCT05604885
  26. ↑ Zhou Y, Rui L (June 2013). "Leptin signaling and leptin resistance". Frontiers of Medicine. 7 (2): 207–22. doi:10.1007/s11684-013-0263-5. PMC   4069066 . PMID   23580174.
  27. 1 2 Klok MD, Jakobsdottir S, Drent ML (January 2007). "The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review". Obesity Reviews. 8 (1): 21–34. doi:10.1111/j.1467-789x.2006.00270.x. PMID   17212793. S2CID   24266123.
  28. ↑ Nunziata A, Borck G, Funcke JB, Kohlsdorf K, Brandt S, Hinney A, Moepps B, Gierschik P, Debatin KM, Fischer-Posovszky P, Wabitsch M (November 2017). "Estimated prevalence of potentially damaging variants in the leptin gene". Molecular and Cellular Pediatrics. 4 (1): 10. doi:10.1186/s40348-017-0074-x. PMC   5670095 . PMID   29101506.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.