Alternative titles; symbols
HGNC Approved Gene Symbol: MCHR1
Cytogenetic location: 22q13.2 Genomic coordinates (GRCh38): 22:40,679,484-40,682,812 (from NCBI)
The MCHR1 gene encodes a G protein-coupled receptor for melanin-concentrating hormone (MCH; 176795), a cyclic peptide that regulates a variety of functions in the mammalian brain, in particular feeding behavior (Saito et al., 1999).
By searching EST databases for sequences encoding G protein-coupled receptors, Kolakowski et al. (1996) identified an EST sequence with significant homology to the somatostatin receptors (SSTRs see, e.g., 182451). They cloned the gene corresponding to this EST from a human genomic library. Sequencing of a genomic clone, which they termed SLC1, revealed an open reading frame encoding a 402-amino acid protein. Its transmembrane regions are approximately 40% identical to other members of the SSTR family, including several residues considered to form the ligand-binding pocket of SSTRs. Northern blot analysis detected a single 2.4-kb transcript with greatest abundance in the human brain, particularly in the frontal cortex and hypothalamus. These regions are associated with emotion, memory, and sensory perception. Kolakowski et al. (1996) expressed the SLC1 receptor in COS-7 cells and found that it does not bind to somatostatin peptides. They identified a polymorphic CA repeat in the 5-prime untranslated region of this gene.
Lakaye et al. (1998) cloned the rat Slc1 gene. They found that the rat gene encodes a protein of 353 amino acids and that the human cDNA described by Kolakowski et al. (1996) had an extracellular N terminus 49 amino acids longer than that of the rat. On the basis of the sequence of a 128-kb fragment of chromosome 22 encompassing the SLC1 gene, Lakaye et al. (1998) deduced a corrected amino acid sequence for the human receptor. Both rat and human SLC1 receptors are 353 amino acids long with 3 consensus N-glycosylation sites. They share 96% amino acid sequence identity.
Because the human SLC1 sequence obtained by Kolakowski et al. (1996) was deduced from genomic DNA, Lakaye et al. (1998) suspected the presence of an intron in the gene. They confirmed this by PCR using primer spanning the intron.
Chambers et al. (1999) used a reverse pharmacology approach to identify the natural cognate ligand for SLC1. They expressed the receptor in HEK293 cells and screened against a large library of known bioactive substances, including over 500 naturally occurring or putative neuropeptides. In this screen, melanin-concentrating hormone (MCH; 176795) was the only substance to produce a robust, dose-dependent (EC-50 = 3.72 nM), transient elevation of intracellular calcium in HEK293 cells transiently transfected with SLC1. MCH stimulates feeding when injected directly into rat brains. The mRNA for MCH precursor is upregulated in the hypothalamus of genetically obese mice and in fasted animals, and mice lacking MCH eat less and are lean. MCH antagonist might therefore provide a treatment for obesity.
MCH can act as a functional antagonist of alpha-melanocyte-stimulating hormone (alpha-MSH; see POMC, 176830) in a diverse range of animal species and physiologic roles. In mammals, MCH is orexigenic and alpha-MSH is anorexigenic. Chambers et al. (1999) tested alpha-MSH at up to 10-mM concentration and no agonistic or antagonistic interaction with SLC1 was observed. Together with the observation that MCH could not displace alpha-MSH from melanocortin receptors, these results supported the idea that the functional, mutually antagonistic effects of alpha-MSH and MCH are mediated by their interaction at separate receptors. These observations are consistent with the general observation that neuropeptides that inhibit food intake all act by increasing protein kinase A (see 176911) signaling, whereas peptides that potently increase food intake, for example neuropeptide Y (162640) and agouti-related protein (602311), appear to act in general by reducing intracellular protein kinase A signaling. Using in situ hybridization, Chambers et al. (1999) demonstrated that SLC1 is widely and strongly expressed in the rat brain. There were clear mRNA signals in the olfactory tubercle, cerebral cortex, substantia nigra, basal forebrain, CA1, CA2, and CA3 fields of the hippocampus, amygdala, and various other nuclei in the hypothalamus, thalamus, midbrain, and hindbrain. There were also strong signals in the ventromedial and dorsomedial nuclei of the hypothalamus, areas widely recognized as being involved in feeding behavior.
Saito et al. (1999) identified SLC1 as an MCH hormone receptor using a different technique and found similar EC-50 and brain distribution for MCHR1 (SLC1).
Takahashi et al. (2001) studied expression of MCHR mRNA by RT-PCR and Northern blot analyses. RT-PCR analysis showed that MCHR mRNA was widely expressed in brain tissues, pituitary, normal portions of adrenal glands (cortex and medulla), tumor tissues of adrenocortical tumors (12 of 13 cases), pheochromocytoma (all 7 cases), ganglioneuroblastoma (1 case), neuroblastoma (all 5 cases), and various cultured tumor cell lines (6 of 7 cell lines), including 2 neuroblastoma cell lines. Northern blot analysis showed the expression of MCHR mRNA only in the tumor tissues of 5 pheochromocytomas, 1 ganglioneuroblastoma, and 4 neuroblastomas, indicating that the expression levels of MCHR mRNA are much higher in these tumors than in the other tissues. The authors concluded that MCH or MCH-like peptides may be related to the pathophysiology of these neural crest-derived tumors.
Borowsky et al. (2002) showed that the selective high-affinity MCH1R receptor antagonist SNAP-7941 inhibited food intake stimulated by central administration of MCH, reduced consumption of palatable food, and after chronic administration to rats with diet-induced obesity, resulted in a marked, sustained decrease in body weight. Borowsky et al. (2002) also showed that SNAP-7941 produced effects similar to clinically used antidepressants and anxiolytics in 3 animal models of depression/anxiety: the rat forced-swim test, rat social interaction, and guinea pig maternal-separation vocalization tests. Given these observations, Borowsky et al. (2002) concluded that an MCH1R antagonist may be useful not only in the management of obesity but also as a treatment for depression and/or anxiety.
Kolakowski et al. (1996) mapped the SLC1 gene to chromosome 22q13.3 by fluorescence in situ hybridization.
Marsh et al. (2002) evaluated the physiologic role of MCH1R by generating deficient (Mch1r -/-) mice. The null mice had normal body weights, yet were lean and had reduced fat mass. Surprisingly, the null mice were hyperphagic when maintained on regular chow, and their leanness was a consequence of hyperactivity and altered metabolism. Consistent with the hyperactivity, the null mice were less susceptible to diet-induced obesity. Chronic central infusions of melanin-concentrating hormone induced hyperphagia and mild obesity in wildtype mice, but not in the Mch1r -/- mice. Marsh et al. (2002) concluded that melanin-concentrating hormone receptor-1 is a physiologically relevant MCH receptor in mice and plays a role in energy homeostasis through multiple actions on locomotor activity, metabolism, appetite, and neuroendocrine function.
Borowsky, B., Durkin, M. M., Ogozalek, K., Marzabadi, M. R., DeLeon, J., Lagu, B., Heurich, R., Lichtblau, H., Shaposhnik, Z., Daniewska, I., Blackburn, T. P., Branchek, T. A., Gerald, C., Vaysse, P. J., Forray, C. Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist. Nature Med. 8: 825-830, 2002. Note: Erratum: Nature Med. 8: 639 only, 2002. [PubMed: 12118247] [Full Text: https://doi.org/10.1038/nm741]
Chambers, J., Ames, R. S., Bergsma, D., Muir, A., Fitzgerald, L. R., Hervieu, G., Dytko, G. M., Foley, J. J., Martin, J., Liu, W.-S., Park, J., Ellis, C., Ganguly, S., Konchar, S., Cluderay, J., Leslie, R., Wilson, S., Sarau, H. M. Melanin-concentrating hormone is the cognate-ligand for the orphan G-protein-coupled receptor SLC-1. Nature 400: 261-265, 1999. [PubMed: 10421367] [Full Text: https://doi.org/10.1038/22313]
Kolakowski, L. F., Jr., Jung, B. P., Nguyen, T., Johnson, M. P., Lynch, K. R., Cheng, R., Heng, H. H. Q., George, S. R., O'Dowd, B. F. Characterization of a human gene related to genes encoding somatostatin receptors. FEBS Lett. 398: 253-258, 1996. [PubMed: 8977118] [Full Text: https://doi.org/10.1016/s0014-5793(96)01160-x]
Lakaye, B., Minet, A., Zorzi, W., Grisar, T. Cloning of the rat brain cDNA encoding for the SLC-1 G protein-coupled receptor reveals the presence of an intron in the gene. Biochim. Biophys. Acta 1401: 216-220, 1998. [PubMed: 9531978] [Full Text: https://doi.org/10.1016/s0167-4889(97)00135-3]
Marsh, D. J., Weingarth, D. T., Novi, D. E., Chen, H. Y., Trumbauer, M. E., Chen, A. S., Guan, X.-M., Jiang, M. M., Feng, Y., Camacho, R. E., Shen, Z., Frazier, E. G., and 10 others. Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. Proc. Nat. Acad. Sci. 99: 3240-3245, 2002. [PubMed: 11867747] [Full Text: https://doi.org/10.1073/pnas.052706899]
Saito, Y., Nothacker, H.-P., Wang, Z., Lin, S. H. S., Leslie, F., Civelli, O. Molecular characterization of the melanin-concentrating-hormone receptor. Nature 400: 265-269, 1999. [PubMed: 10421368] [Full Text: https://doi.org/10.1038/22321]
Takahashi, K., Totsune, K., Murakami, O., Sone, M., Satoh, F., Kitamuro, T., Noshiro, T., Hayashi, Y., Sasano, H., Shibahara, S. Expression of melanin-concentrating hormone receptor messenger ribonucleic acid in tumor tissues of pheochromocytoma, ganglioneuroblastoma, and neuroblastoma. J. Clin. Endocr. Metab. 86: 369-374, 2001. [PubMed: 11232026] [Full Text: https://doi.org/10.1210/jcem.86.1.7158]