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Gene Review

Mc4r  -  melanocortin 4 receptor

Rattus norvegicus

Synonyms: MC4-R, Melanocortin receptor 4
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Disease relevance of Mc4r


Psychiatry related information on Mc4r

  • Rats were fasted overnight to promote feeding behavior, then injected intraperitoneally with LPS (100 micrograms/kg ip), followed 30 min later by intracerebroventricular injection of either alpha-MSH or the melanocortin receptor subtype 3/subtype 4 (MC3-R/MC4-R) antagonist SHU-9119 [6].
  • The production of alpha-MSH is reduced during food deprivation, but MC4-R density is increased [7].
  • Moreover, the results demonstrate that cocaine treatment increases behavioral responses (grooming and locomotor activity) to infusions of a melanocortin agonist, indicating that up-regulation of MC4-R expression results in functional consequences [8].
  • Anxiolytic-like effect of a selective and non-peptidergic melanocortin 4 receptor antagonist, MCL0129, in a social interaction test [9].

High impact information on Mc4r

  • Yet, the highest MC4-R density in the brain is found in the dorsal motor nucleus of the vagus nerve, situated subjacent to the commissural nucleus of the solitary tract, a site of pro-opiomelanocortin mRNA expression [10].
  • Overall, this study demonstrated that MC3R and MC4R have distinct signaling in either the cAMP- or the inositol phospholipid-mediated pathway with different conformational requirements [11].
  • Using a luciferase reporter gene under the transcriptional control of a cAMP- responsive element (CRE), the coupling efficiency of the MC4R and MC3R to G-proteins was previously shown to be different [11].
  • Chronic central melanocortin-4 receptor antagonism and central neuropeptide-Y infusion in rats produce increased adiposity by divergent pathways [12].
  • To determine whether similar hormonal and metabolic mechanisms are involved in these two obesity syndromes, we investigated the time course of effects induced by 6-day intracerebroventricular (ICV) infusion of NPY (3.5 nmol/day) or the MC4 receptor antagonist HS014 (4.8 nmol/day) in rats pair-fed with vehicle-infused controls [12].

Chemical compound and disease context of Mc4r

  • Ten structurally similar melanocortin subtype-4 receptor (MC4R) ligands from an aryl piperazine chemical platform were evaluated in female Fischer 344 rats to assess the toxicity of this class of compounds [13].

Biological context of Mc4r


Anatomical context of Mc4r


Associations of Mc4r with chemical compounds

  • MTII (0.5 nmol)-induced increase in plasma corticosterone was attenuated by the selective MC4R antagonist HS014 (0.25-1.0 nmol) and nonselective CRH receptor antagonist alpha-helical-CRH9-41 (0.125-0.5 nmol) in a dose-dependent manner [19].
  • Rats were habituated to the test environment and injection procedure and then received intracerebroventicular injections of various combinations of the MCR4 receptor antagonist JKC-363, the CB(1) receptor agonist Delta(9)-tetrahydrocannabinol, the MCR4 receptor agonist alpha-MSH, or the cannabinoid CB(1) receptor antagonist SR 141716 [20].
  • Activation of central melanocortin-4 receptor suppresses lipopolysaccharide-induced fever in rats [4].
  • We have previously demonstrated that stimulation or blockade of MC4-R, achieved by the same drug dosage as in this study, significantly affect luteinizing hormone and prolactin secretion in rats [21].
  • We examined hypothalamic gene expression of Ob-Rb, NPY, POMC, MC4-R, and AgRP in intact Wistar rats treated with estradiol for 48 hours [22].

Regulatory relationships of Mc4r


Other interactions of Mc4r

  • We investigated endogenous melanocortin ligand binding and activation at the MC3-R and MC4-R and their effects on feeding [14].
  • In the present study, we investigated the effect of acute and chronic morphine administration on the level of CRF1 and melanocortin 4 receptor (MC4-R) mRNAs in the rat amygdala by quantitative real-time PCR method [17].
  • In the amygdala, the expression of MC4R and POMC mRNA as well as CRF mRNA was significantly increased by electrical foot shock stress [15].
  • Pivotal roles of alpha-melanocyte-stimulating hormone and the melanocortin 4 receptor in leptin stimulation of prolactin secretion in rats [27].
  • Agouti-related protein (Agrp) (83-132), a biologically active fragment of the endogenous MC4-R antagonist, administered ICV at a dose of 1 nmol completely blocked the anorectic effect of 1 nmol alpha-MSH [28].

Analytical, diagnostic and therapeutic context of Mc4r

  • To better understand the interplay between the AGRP and melanocortin signaling systems, we compared their nerve fiber distributions with each other by immunohistochemistry and their perikarya distribution with MC3R and MC4R by double in situ hybridization [29].
  • Using RT-PCR and ribonuclease protection assays, we determined that MC4-R mRNA is also expressed in adult rat heart, lung, kidney, and testis [30].
  • MC3-R and MC4-R were measured by quantitative autoradiography in brain sections using 125I-labeled Nle4-D-Phe7-alpha-MSH (125I-NDP-MSH) and discriminated by masking MC3-R with excess unlabelled gamma2-MSH [24].
  • Moreover, immobilization stress-induced anorexia may be partially reversed by single and repeated intracerebroventricular administration of selective MC4 receptor antagonists [31].
  • To explore the possibility that the DMX contributes to 4th-icv MC4-R effects, we delivered doses of MTII and SHU9119 that are subthreshold for ventricular response unilaterally through a cannula centered above the DMX [32].


  1. Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat. Kishi, T., Aschkenasi, C.J., Lee, C.E., Mountjoy, K.G., Saper, C.B., Elmquist, J.K. J. Comp. Neurol. (2003) [Pubmed]
  2. Melanocortin-4 receptor messenger RNA expression is up-regulated in the non-damaged striatum following unilateral hypoxic-ischaemic brain injury. Mountjoy, K.G., Guan, J., Elia, C.J., Sirimanne, E.S., Williams, C.E. Neuroscience (1999) [Pubmed]
  3. Melanocortin 4 receptor is expressed in the dorsal root ganglions and down-regulated in neuropathic rats. Starowicz, K., Bilecki, W., Sieja, A., Przewlocka, B., Przewlocki, R. Neurosci. Lett. (2004) [Pubmed]
  4. Activation of central melanocortin-4 receptor suppresses lipopolysaccharide-induced fever in rats. Sinha, P.S., Schiöth, H.B., Tatro, J.B. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2003) [Pubmed]
  5. Melanocortin antagonists define two distinct pathways of cardiovascular control by alpha- and gamma-melanocyte-stimulating hormones. Li, S.J., Varga, K., Archer, P., Hruby, V.J., Sharma, S.D., Kesterson, R.A., Cone, R.D., Kunos, G. J. Neurosci. (1996) [Pubmed]
  6. Role of central melanocortins in endotoxin-induced anorexia. Huang, Q.H., Hruby, V.J., Tatro, J.B. Am. J. Physiol. (1999) [Pubmed]
  7. Food deprivation decreases responsiveness of ventromedial hypothalamic neurons to melanocortins. Li, Y.Z., Davidowa, H. J. Neurosci. Res. (2004) [Pubmed]
  8. Molecular and behavioral interactions between central melanocortins and cocaine. Alvaro, J.D., Taylor, J.R., Duman, R.S. J. Pharmacol. Exp. Ther. (2003) [Pubmed]
  9. Anxiolytic-like effect of a selective and non-peptidergic melanocortin 4 receptor antagonist, MCL0129, in a social interaction test. Shimazaki, T., Chaki, S. Pharmacol. Biochem. Behav. (2005) [Pubmed]
  10. Brainstem application of melanocortin receptor ligands produces long-lasting effects on feeding and body weight. Grill, H.J., Ginsberg, A.B., Seeley, R.J., Kaplan, J.M. J. Neurosci. (1998) [Pubmed]
  11. Identification of domains directing specificity of coupling to G-proteins for the melanocortin MC3 and MC4 receptors. Kim, C.S., Lee, S.H., Kim, R.Y., Kim, B.J., Li, S.Z., Lee, I.H., Lee, E.J., Lim, S.K., Bae, Y.S., Lee, W., Baik, J.H. J. Biol. Chem. (2002) [Pubmed]
  12. Chronic central melanocortin-4 receptor antagonism and central neuropeptide-Y infusion in rats produce increased adiposity by divergent pathways. Baran, K., Preston, E., Wilks, D., Cooney, G.J., Kraegen, E.W., Sainsbury, A. Diabetes (2002) [Pubmed]
  13. Gastric mucosal damage following repeat administration of melanocortin subtype-4 receptor ligands to Fischer 344 rats. Williams, T.M., Donnelly, K.B. Toxicologic pathology (2006) [Pubmed]
  14. Investigation of the melanocyte stimulating hormones on food intake. Lack Of evidence to support a role for the melanocortin-3-receptor. Abbott, C.R., Rossi, M., Kim, M., AlAhmed, S.H., Taylor, G.M., Ghatei, M.A., Smith, D.M., Bloom, S.R. Brain Res. (2000) [Pubmed]
  15. Regulation of CRF, POMC and MC4R gene expression after electrical foot shock stress in the rat amygdala and hypothalamus. Yamano, Y., Yoshioka, M., Toda, Y., Oshida, Y., Chaki, S., Hamamoto, K., Morishima, I. J. Vet. Med. Sci. (2004) [Pubmed]
  16. Brainstem melanocortin 3/4 receptor stimulation increases uncoupling protein gene expression in brown fat. Williams, D.L., Bowers, R.R., Bartness, T.J., Kaplan, J.M., Grill, H.J. Endocrinology (2003) [Pubmed]
  17. The effect of morphine on MC4 and CRF receptor mRNAs in the rat amygdala and attenuation of tolerance after their blockade. Starowicz, K., Sieja, A., Bilecki, W., Obara, I., Przewlocka, B. Brain Res. (2003) [Pubmed]
  18. Different developmental patterns of melanocortin MC3 and MC4 receptor mRNA: predominance of Mc4 in fetal rat nervous system. Kistler-Heer, V., Lauber, M.E., Lichtensteiger, W. J. Neuroendocrinol. (1998) [Pubmed]
  19. Interaction between alpha-melanocyte-stimulating hormone and corticotropin-releasing hormone in the regulation of feeding and hypothalamo-pituitary-adrenal responses. Lu, X.Y., Barsh, G.S., Akil, H., Watson, S.J. J. Neurosci. (2003) [Pubmed]
  20. Evidence for an interaction between CB1 cannabinoid and melanocortin MCR-4 receptors in regulating food intake. Verty, A.N., McFarlane, J.R., McGregor, I.S., Mallet, P.E. Endocrinology (2004) [Pubmed]
  21. Evaluation of the role of melanocortin 3 and 4 receptors in leptin-stimulated and spontaneous growth hormone secretion in rats. Watanobe, H., Yoneda, M. Neuroendocrinology (2003) [Pubmed]
  22. Physiologic estradiol levels enhance hypothalamic expression of the long form of the leptin receptor in intact rats. Rocha, M., Bing, C., Williams, G., Puerta, M. J. Nutr. Biochem. (2004) [Pubmed]
  23. Corticotropin-releasing factor (CRF) induced anorexia is not influenced by a melanocortin 4 receptor blockage. Vergoni, A.V., Bertolini, A., Wikberg, J.E., Schiöth, H.B. Peptides (1999) [Pubmed]
  24. Altered energy balance causes selective changes in melanocortin-4(MC4-R), but not melanocortin-3 (MC3-R), receptors in specific hypothalamic regions: further evidence that activation of MC4-R is a physiological inhibitor of feeding. Harrold, J.A., Widdowson, P.S., Williams, G. Diabetes (1999) [Pubmed]
  25. Alpha-melanocyte-stimulating hormone through melanocortin-4 receptor inhibits nitric oxide synthase and cyclooxygenase expression in the hypothalamus of male rats. Caruso, C., Mohn, C., Karara, A.L., Rettori, V., Watanobe, H., Schiöth, H.B., Seilicovich, A., Lasaga, M. Neuroendocrinology (2004) [Pubmed]
  26. Orexigenic effect of the melanocortin MC4 receptor antagonist HS014 is inhibited only partially by neuropeptide Y Y1 receptor selective antagonists. Kask, A., Schiöth, H.B., Harro, J., Wikberg, J.E., Rägo, L. Can. J. Physiol. Pharmacol. (2000) [Pubmed]
  27. Pivotal roles of alpha-melanocyte-stimulating hormone and the melanocortin 4 receptor in leptin stimulation of prolactin secretion in rats. Watanobe, H., Schiöth, H.B., Izumi, J. J. Neurochem. (2003) [Pubmed]
  28. Cocaine- and amphetamine-regulated transcript, glucagon-like peptide-1 and corticotrophin releasing factor inhibit feeding via agouti-related protein independent pathways in the rat. Edwards, C.M., Abbott, C.R., Sunter, D., Kim, M., Dakin, C.L., Murphy, K.G., Abusnana, S., Taheri, S., Rossi, M., Bloom, S.R. Brain Res. (2000) [Pubmed]
  29. Anatomy of an endogenous antagonist: relationship between Agouti-related protein and proopiomelanocortin in brain. Bagnol, D., Lu, X.Y., Kaelin, C.B., Day, H.E., Ollmann, M., Gantz, I., Akil, H., Barsh, G.S., Watson, S.J. J. Neurosci. (1999) [Pubmed]
  30. Melanocortin-4 receptor messenger ribonucleic acid expression in rat cardiorespiratory, musculoskeletal, and integumentary systems. Mountjoy, K.G., Jenny Wu, C.S., Dumont, L.M., Wild, J.M. Endocrinology (2003) [Pubmed]
  31. Melanocortins and feeding behavior. Vergoni, A.V., Schiöth, H.B., Bertolini, A. Biomed. Pharmacother. (2000) [Pubmed]
  32. The role of the dorsal vagal complex and the vagus nerve in feeding effects of melanocortin-3/4 receptor stimulation. Williams, D.L., Kaplan, J.M., Grill, H.J. Endocrinology (2000) [Pubmed]
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