|Coordinate||81,237,868 bp (GRCm38)|
|Base Change||A ⇒ G (forward strand)|
|Gene Name||melanin-concentrating hormone receptor 1|
|Synonym(s)||melanin-concentrating hormone receptor 1, Gpr24-9, Gpr24, Mch1r, MCH-1R|
|Chromosomal Location||81,235,499-81,238,964 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene, a member of the G protein-coupled receptor family 1, is an integral plasma membrane protein which binds melanin-concentrating hormone. The encoded protein can inhibit cAMP accumulation and stimulate intracellular calcium flux, and is probably involved in the neuronal regulation of food consumption. Although structurally similar to somatostatin receptors, this protein does not seem to bind somatostatin. [provided by RefSeq, Jul 2008]
PHENOTYPE: Homozygous mice for some alleles may display osteoporosis, resistance to diet-induced obesity, abnormal pyramidal neuron physiology, hyperactivity, polyphagia, increased heart rate and body temperature, sleep behavior, and impaired conditioned learning. [provided by MGI curators]
|Amino Acid Change||Tyrosine changed to Cysteine|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000126191]|
AA Change: Y273C
|Predicted Effect||probably damaging
PolyPhen 2 Score 0.999 (Sensitivity: 0.14; Specificity: 0.99)
|Meta Mutation Damage Score||0.7303|
|Is this an essential gene?||Probably nonessential (E-score: 0.102)|
|Candidate Explorer Status||CE: good candidate; Verification probability: 0.477; ML prob: 0.472; human score: -4.5|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Unknown|
|Last Updated||2019-09-04 9:32 PM by Anne Murray|
|Record Created||2019-01-03 12:51 AM by Bruce Beutler|
The Ketogenic phenotype was identified among G3 mice of the pedigree R6516, some of which showed reduced body weights compared to wild-type littermates (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 64 mutations. The body weight phenotype was linked to a mutation in Mchr1: an A to G transition at base pair 81,237,868 (v38) on chromosome 15, or base pair 2,370 in the GenBank genomic region NC_000081. The strongest association was found with an additive model of inheritance, wherein 11 variant homozygotes and 34 heterozygous mice departed phenotypically from 25 homozygous reference mice with a P value of 2.095 x 10-5 (Figure 2).
The mutation corresponds to residue 1,093 in the mRNA sequence NM_145132 within exon 2 of 2 total exons.
The mutated nucleotide is indicated in red. The mutation results in a tyrosine to cysteine substitution at position 273 (Y273C) in the MCHR1 protein, and is strongly predicted by Polyphen-2 to cause loss of function (score = 0.999).
|Illustration of Mutations in
Gene & Protein
Mchr1 encodes melanin-concentrating hormone (MCH) receptor 1 (MCHR1; alternatively, MCH-1R, SLC-1, or GPR24), a G protein-coupled receptor (GPCR). MCHR1 belongs to the γ-group of rhodopsin (see the record for bemr3) family class A GPCRs. GPCRs have seven transmembrane helices connected by loops, and ligand binding occurs at extracellular loops facilitated by specific transmembrane helices (Figure 3). The N-terminus is extracellular, while the C-terminus is intracellular. As a GPCR, MCHR1 couples with a heterotrimeric G protein (Gi/o and Gq) to mediate its downstream effects. G proteins consist of an α subunit that binds and hydrolyzes GTP (Gα), and β and γ subunits that are constitutively associated in a complex. In the absence of a stimulus, the GDP-bound α subunit and the βγ complex are associated (Figure 4). Upon activation by ligand binding, the GPCR recruits its cognate heterotrimeric G protein, and undergoes a conformational change enabling it to act as guanine nucleotide exchange factor (GEF) for the G protein α subunit. GEFs promote the exchange of GDP for GTP, resulting in dissociation of the GTP-bound α subunit from the activated receptor and the βγ complex. Both the GTP-bound α subunit and the βγ complex mediate signaling by modulating the activities of other proteins, such as adenylyl cyclases, phospholipases, and ion channels. Gα signaling is terminated upon GTP hydrolysis, an activity intrinsic to Gα and one that may be stimulated by GTPase activating proteins (GAPs) such as regulators of G protein signaling (RGS) proteins. The GDP-bound Gα subunit reassociates with the βγ complex and is ready for another activation cycle.
The essentiality of several amino acids throughout the length of MCHR1 has been determined. For example, multiple residues in the second intracellular loop (i.e., amino acids 150 to 158), third intracellular loop (i.e., amino acids 234, 242, 243, and 257), and fifth transmembrane domain (i.e., amino acids 228 and 229) are responsible for determining the Gi/o versus Gq G protein preference (1). Mutation of the residues results in impaired Gi/o activation, but does not affect Gq activation. Asp123 within the third transmembrane domain is required for ligand binding (2). Arg155 within the second intracellular loop is required for GPCR-associated signaling (3). An Asp-Arg-Tyr (DRY) motif (amino acids 140 to 142) regulates receptor conformation and dual G protein coupling (4). Pro377 and Arg210 are required for MCH-associated signaling (5). P377S and R210H mutations, which have been identified in underweight individuals, resulted in a failure to response to MCH, but did not alter cell surface expression of MCHR1. Within the C-terminal tail, Arg319 and Lys320 are essential for Gi/o- and Gq-mediated signaling (6), while Thr317, Ser325, and Thr342 are required for MCH-induced receptor internalization (7;8).
MCHR1 undergoes several post-translational modifications. N-linked glycosylation of Asn13, Asn16, and Asn23 is required for MCHR1 trafficking to the cell surface (9). MCHR1 has nine predicted phosphorylation sites: Ser158 and Thr255 (by protein kinase A); Ser151, Ser243, Ser246, Thr251, Thr317, and Ser325 (by protein kinase C); and Thr342 (by casein kinase 2) (7). Phosphorylation of Thr317, Ser325, and Thr342 regulate MCH-induced receptor internalization (8). Phosphorylation of Thr255, at the junction of the third intracellular loop and sixth transmembrane domain, is necessary for receptor folding and trafficking to the cell surface (10). The significance of the other putative phosphorylation sites is unknown.
Several proteins interact with MCHR1, including periplakin, neurochondrin, and RGS8. Periplakin and neurochondrin interact with the proximal C-terminus, reducing calcium mobilization initiation (11;12). RGS8 is a GTPase-activating protein for Gα subunits that interacts with Arg253 and Arg256 within the distal end of the third cytoplasmic loop of MCHR1, negatively regulating MCHR1 function (13).
The Ketogenic mutation results in a tyrosine to cysteine substitution at position 273 (Y273C). Amino acid 273 is within the sixth transmembrane domain.
MCHR1 is predominantly expressed in the brain (1;14;15). MCHR1 is also expressed in pituitary and adrenal glands as well as tumor tissues of adrenocortical tumors, pheochromocytoma, ganglioneuroblastoma, and neuroblastoma (15). MCHR1 mRNA in rats was expressed in the olfactory nerve layer, olfactory nucleus, tubercle, hippocampal formation, septum, amygdala, and nucleus accumbens shell (16).
MCHR1 is a receptor for MCH, a neuropeptide (1;17). MCH functions in several behaviors, including feeding, body weight regulation, anxiety, sleep regulation, and reward behavior. MCHR1 stimulation results in activation of several signaling pathways, resulting in calcium mobilization (via the Gi/o- and Gq-coupled pathways), ERK phosphorylation, and inhibition of cyclic AMP generation (via the Gi/o-coupled pathway) (Figure 5) (1;17;18).
Overall, loss of MCH-associated signaling in the mouse results in increased locomotor activity, aggression, and male sexual behavior as well as suppression of non-REM sleep, anxiety, responses to novelty, startle responses, and conditioned place preferences (19-22). Loss of MCH-associated signaling also results in increased food intake, body temperature, activity, oxygen consumption, heart rate, and mean arterial pressure as well as suppression of body weight, fat mass, and plasma leptin levels (for more information about leptin, see the record for potbelly) (19-26). Most Mchr1-deficient (Mchr1-/-) mouse models showed reduced susceptibility to diet-induced obesity and increased weight loss in response to food deprivation compared to wild-type mice (24-29). Mchr1-/- mice showed increased foraging behaviors as well as more food-directed responses when the response requirement to obtain food was increased (30). Some Mchr1-/- mice showed reduced circulating levels of iodothyronine with concomitant increased levels of thyrotropin-releasing hormone and thyrotropin-releasing factor, indicating aberrant thyroid function (31). Both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptor-mediated transmissions were reduced in the Mchr1-/- mice (32). Also, long-term synaptic potentiation and long-term synaptic depression were reduced in the Mchr1-/- mice (32).
The reduced body weight phenotype observed in the Ketogenic mice mimics that observed in Mchr1-/- mice, indicating loss of MCHR1-associated function. MCHR1-associated signaling results in increased Lep mRNA synthesis and leptin secretion. Although the Mchr1-/- mice have increased food intake, body weight gain, fat mass, and plasma leptin levels are suppressed. Leptin is a hormone that regulates several functions in the body (see potbelly), including regulation of energy expenditure, food intake, weight loss, and diabetes (Figure 6).
1) 94°C 2:00
The following sequence of 499 nucleotides is amplified (chromosome 15, + strand):
1 actcctgtgt ggctctatgc caggcttatc cccttcccag ggggtgctgt gggctgtggc
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
1. Saito, Y., Nothacker, H. P., Wang, Z., Lin, S. H., Leslie, F., and Civelli, O. (1999) Molecular Characterization of the Melanin-Concentrating-Hormone Receptor. Nature. 400, 265-269.
2. Macdonald, D., Murgolo, N., Zhang, R., Durkin, J. P., Yao, X., Strader, C. D., and Graziano, M. P. (2000) Molecular Characterization of the Melanin-Concentrating hormone/receptor Complex: Identification of Critical Residues Involved in Binding and Activation. Mol Pharmacol. 58, 217-225.
3. Saito, Y., Tetsuka, M., Saito, S., Imai, K., Yoshikawa, A., Doi, H., and Maruyama, K. (2005) Arginine Residue 155 in the Second Intracellular Loop Plays a Critical Role in Rat Melanin-Concentrating Hormone Receptor 1 Activation. Endocrinology. 146, 3452-3462.
4. Aizaki, Y., Maruyama, K., Nakano-Tetsuka, M., and Saito, Y. (2009) Distinct Roles of the DRY Motif in Rat Melanin-Concentrating Hormone Receptor 1 in Signaling Control. Peptides. 30, 974-981.
5. Goldstein, C., Schroeder, J. C., Fortin, J. P., Goss, J. M., Schaus, S. E., Beinborn, M., and Kopin, A. S. (2010) Two Naturally Occurring Mutations in the Type 1 Melanin-Concentrating Hormone Receptor Abolish Agonist-Induced Signaling. J Pharmacol Exp Ther. 335, 799-806.
6. Tetsuka, M., Saito, Y., Imai, K., Doi, H., and Maruyama, K. (2004) The Basic Residues in the Membrane-Proximal C-Terminal Tail of the Rat Melanin-Concentrating Hormone Receptor 1 are Required for Receptor Function. Endocrinology. 145, 3712-3723.
7. Saito, Y., Hamamoto, A., and Kobayashi, Y. (2013) Regulated Control of Melanin-Concentrating Hormone Receptor 1 through Posttranslational Modifications. Front Endocrinol (Lausanne). 4, 154.
8. Saito, Y., Tetsuka, M., Li, Y., Kurose, H., and Maruyama, K. (2004) Properties of Rat Melanin-Concentrating Hormone Receptor 1 Internalization. Peptides. 25, 1597-1604.
9. Saito, Y., Tetsuka, M., Yue, L., Kawamura, Y., and Maruyama, K. (2003) Functional Role of N-Linked Glycosylation on the Rat Melanin-Concentrating Hormone Receptor 1. FEBS Lett. 533, 29-34.
10. Fan, J., Perry, S. J., Gao, Y., Schwarz, D. A., and Maki, R. A. (2005) A Point Mutation in the Human Melanin Concentrating Hormone Receptor 1 Reveals an Important Domain for Cellular Trafficking. Mol Endocrinol. 19, 2579-2590.
11. Francke, F., Ward, R. J., Jenkins, L., Kellett, E., Richter, D., Milligan, G., and Bachner, D. (2006) Interaction of Neurochondrin with the Melanin-Concentrating Hormone Receptor 1 Interferes with G Protein-Coupled Signal Transduction but Not Agonist-Mediated Internalization. J Biol Chem. 281, 32496-32507.
12. Murdoch, H., Feng, G. J., Bachner, D., Ormiston, L., White, J. H., Richter, D., and Milligan, G. (2005) Periplakin Interferes with G Protein Activation by the Melanin-Concentrating Hormone Receptor-1 by Binding to the Proximal Segment of the Receptor C-Terminal Tail. J Biol Chem. 280, 8208-8220.
13. Miyamoto-Matsubara, M., Saitoh, O., Maruyama, K., Aizaki, Y., and Saito, Y. (2008) Regulation of Melanin-Concentrating Hormone Receptor 1 Signaling by RGS8 with the Receptor Third Intracellular Loop. Cell Signal. 20, 2084-2094.
14. Kolakowski, L. F.,Jr, Jung, B. P., Nguyen, T., Johnson, M. P., Lynch, K. R., Cheng, R., Heng, H. H., George, S. R., and O'Dowd, B. F. (1996) Characterization of a Human Gene Related to Genes Encoding Somatostatin Receptors. FEBS Lett. 398, 253-258.
15. Takahashi, K., Totsune, K., Murakami, O., Sone, M., Satoh, F., Kitamuro, T., Noshiro, T., Hayashi, Y., Sasano, H., and Shibahara, S. (2001) Expression of Melanin-Concentrating Hormone Receptor Messenger Ribonucleic Acid in Tumor Tissues of Pheochromocytoma, Ganglioneuroblastoma, and Neuroblastoma. J Clin Endocrinol Metab. 86, 369-374.
16. Saito, Y., Cheng, M., Leslie, F. M., and Civelli, O. (2001) Expression of the Melanin-Concentrating Hormone (MCH) Receptor mRNA in the Rat Brain. J Comp Neurol. 435, 26-40.
17. 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., and Sarau, H. M. (1999) Melanin-Concentrating Hormone is the Cognate Ligand for the Orphan G-Protein-Coupled Receptor SLC-1. Nature. 400, 261-265.
18. Hawes, B. E., Kil, E., Green, B., O'Neill, K., Fried, S., and Graziano, M. P. (2000) The Melanin-Concentrating Hormone Receptor Couples to Multiple G Proteins to Activate Diverse Intracellular Signaling Pathways. Endocrinology. 141, 4524-4532.
19. Takase, K., Kikuchi, K., Tsuneoka, Y., Oda, S., Kuroda, M., and Funato, H. (2014) Meta-Analysis of Melanin-Concentrating Hormone Signaling-Deficient Mice on Behavioral and Metabolic Phenotypes. PLoS One. 9, e99961.
20. Ahnaou, A., Dautzenberg, F. M., Huysmans, H., Steckler, T., and Drinkenburg, W. H. (2011) Contribution of Melanin-Concentrating Hormone (MCH1) Receptor to Thermoregulation and Sleep Stabilization: Evidence from MCH1 (-/-) Mice. Behav Brain Res. 218, 42-50.
21. Roy, M., David, N. K., Danao, J. V., Baribault, H., Tian, H., and Giorgetti, M. (2006) Genetic Inactivation of Melanin-Concentrating Hormone Receptor Subtype 1 (MCHR1) in Mice Exerts Anxiolytic-Like Behavioral Effects. Neuropsychopharmacology. 31, 112-120.
22. Brommage, R., Desai, U., Revelli, J. P., Donoviel, D. B., Fontenot, G. K., Dacosta, C. M., Smith, D. D., Kirkpatrick, L. L., Coker, K. J., Donoviel, M. S., Eberhart, D. E., Holt, K. H., Kelly, M. R., Paradee, W. J., Philips, A. V., Platt, K. A., Suwanichkul, A., Hansen, G. M., Sands, A. T., Zambrowicz, B. P., and Powell, D. R. (2008) High-Throughput Screening of Mouse Knockout Lines Identifies True Lean and Obese Phenotypes. Obesity (Silver Spring). 16, 2362-2367.
23. Lalonde, R., and Qian, S. (2007) Exploratory Activity, Motor Coordination, and Spatial Learning in Mchr1 Knockout Mice. Behav Brain Res. 178, 293-304.
24. Astrand, A., Bohlooly-Y, M., Larsdotter, S., Mahlapuu, M., Andersen, H., Tornell, J., Ohlsson, C., Snaith, M., and Morgan, D. G. (2004) Mice Lacking Melanin-Concentrating Hormone Receptor 1 Demonstrate Increased Heart Rate Associated with Altered Autonomic Activity. Am J Physiol Regul Integr Comp Physiol. 287, R749-58.
25. 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., Yu, H., Metzger, J. M., Kuca, S. J., Shearman, L. P., Gopal-Truter, S., MacNeil, D. J., Strack, A. M., MacIntyre, D. E., Van der Ploeg, L. H., and Qian, S. (2002) Melanin-Concentrating Hormone 1 Receptor-Deficient Mice are Lean, Hyperactive, and Hyperphagic and have Altered Metabolism. Proc Natl Acad Sci U S A. 99, 3240-3245.
26. Chen, Y., Hu, C., Hsu, C. K., Zhang, Q., Bi, C., Asnicar, M., Hsiung, H. M., Fox, N., Slieker, L. J., Yang, D. D., Heiman, M. L., and Shi, Y. (2002) Targeted Disruption of the Melanin-Concentrating Hormone Receptor-1 Results in Hyperphagia and Resistance to Diet-Induced Obesity. Endocrinology. 143, 2469-2477.
27. Adamantidis, A., Thomas, E., Foidart, A., Tyhon, A., Coumans, B., Minet, A., Tirelli, E., Seutin, V., Grisar, T., and Lakaye, B. (2005) Disrupting the Melanin-Concentrating Hormone Receptor 1 in Mice Leads to Cognitive Deficits and Alterations of NMDA Receptor Function. Eur J Neurosci. 21, 2837-2844.
28. Adamantidis, A., Salvert, D., Goutagny, R., Lakaye, B., Gervasoni, D., Grisar, T., Luppi, P. H., and Fort, P. (2008) Sleep Architecture of the Melanin-Concentrating Hormone Receptor 1-Knockout Mice. Eur J Neurosci. 27, 1793-1800.
29. Chung, S., Wong, T., Nagasaki, H., and Civelli, O. (2010) Acute Homeostatic Responses to Increased Fat Consumption in MCH1R Knockout Mice. J Mol Neurosci. 42, 459-463.
30. Eiler, W. J.,2nd, Chen, Y., Slieker, L. J., Ardayfio, P. A., Statnick, M. A., and Witkin, J. M. (2017) Consequences of Constitutive Deletion of Melanin-Concentrating Hormone-1 Receptors for Feeding and Foraging Behaviors of Mice. Behav Brain Res. 316, 271-278.
31. Chung, S., Liao, X. H., Di Cosmo, C., Van Sande, J., Wang, Z., Refetoff, S., and Civelli, O. (2012) Disruption of the Melanin-Concentrating Hormone Receptor 1 (MCH1R) Affects Thyroid Function. Endocrinology. 153, 6145-6154.
32. Pachoud, B., Adamantidis, A., Ravassard, P., Luppi, P. H., Grisar, T., Lakaye, B., and Salin, P. A. (2010) Major Impairments of Glutamatergic Transmission and Long-Term Synaptic Plasticity in the Hippocampus of Mice Lacking the Melanin-Concentrating Hormone Receptor-1. J Neurophysiol. 104, 1417-1425.
|Science Writers||Anne Murray|
|Illustrators||Diantha La Vine|
|Authors||Zhao Zhang and Bruce Beutler|