Disease relevance of MCHR1

• Among sera from healthy controls and from patients with autoimmune disease, none exhibited immunoreactivity to MCHR1, indicating a high disease specificity for Ab's against the receptor [1].
• However, similar associations were found when both adults and children were analyzed together (P = 0.006, 0.783 [0.658-0.930]), suggesting that severe forms of obesity with early onset may be associated with SNPs in MCHR1 [2].
• IMR32, a human neuroblastoma cell line, has been shown to express MCHR1 mRNA; however, we were unable to detect either MCH-binding or MCH-stimulated Ca(++)-mobilization in these cells [3].
• Among 106 subjects with severe early onset obesity and a history of hyperphagia, we found two missense variants in MCHR1: Y181H and R248Q [4].
• MCHR1 expression was restricted to melanocytes and melanoma cells [5].

Psychiatry related information on MCHR1

• CONCLUSION: Taken together, we suggest that antagonism of the MCHR1 receptor may provide a novel approach for the treatment of affective disorders, including depression, with a potentially increased efficacy in women [6].
• Melanin-concentrating hormone (MCH) is a cyclic nonadecapeptide involved in the regulation of feeding behavior, which acts through a G protein-coupled receptor (SLC-1) inhibiting adenylcyclase activity [7].
• Thus, the discovery of MCH-R1 antagonists may lead to the development of valuable drugs to treat obesity, anxiety and depressive syndromes [8].
• I have focused particularly on recent data concerning transgenic mice and the ongoing development of MC/MCH receptor antagonists/agonists that may represent promising drugs to treat human eating disorders on both sides of the energy balance (anorexia, obesity) [9].

High impact information on MCHR1

• Here we show that SNAP-7941, a selective, high-affinity MCH1 receptor (MCH1-R) antagonist, 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 [10].
• Given these observations, an MCH1-R antagonist may be useful not only in the management of obesity but also as a treatment for depression and/or anxiety [10].
• The melanin-concentrating hormone receptor 1, a novel target of autoantibody responses in vitiligo [1].
• In contrast to MCHR1, which is intronless in the coding region and is located at the chromosomal locus 22q13.3, the MCHR2 gene has multiple exons and is mapped to locus 6q21 [11].
• MCHR2 has higher protein sequence homology to MCHR1 than any other G protein-coupled receptor [11].

Chemical compound and disease context of MCHR1

• Substituted phenyl biaryl urea derivatives were synthesized and evaluated as MCH-R1 antagonists for the treatment of obesity [12].

Biological context of MCHR1

• In this study, the human MCHR1 gene was extensively characterized by sequencing 3.5 kb of coding, untranslated and intronic regions plus 1 kb of putative promoter region in 180 morbidly obese adults and 87 morbidly obese children, a total of >2.4 Mb of sequencing [2].
• METHODS: We utilized an array of techniques including chronic mild stress (CMS) as a depression paradigm, neurobehavior, gene expression analysis, and knockout genetics to investigate the role of MCH receptor subtype 1 (MCHR1) in murine models of depression [6].
• These data outline the importance of the N-linked glycosylation of the MCHR1 [13].
• CONCLUSION: Our initial association of MCHR1 alleles/haplotype detected might be related to juvenile-onset obesity, conditional on a particular genetic and/or environmental background [14].
• MCHR1 is also a central target of leptin signaling and appears to be a mediator of insulin resistance [15].

Anatomical context of MCHR1

• Thus, we sought to develop a neurally derived cell line endogenously expressing MCHR1 [3].
• MIZIP is expressed in brain, testis and stomach, where expression of MCH and MCH-R1 was previously reported [16].
• We also show that SLC-1 messenger RNA and protein is expressed in the ventromedial and dorsomedial nuclei of the hypothalamus, consistent with a role for SLC-1 in mediating the effects of MCH on feeding [17].
• Comparative pharmacological studies using CHO cells stably expressing either SLC-1 or S643b receptors demonstrated that similar structural features of MCH are required to stimulate intracellular Ca(2+) mobilization at both receptors [18].
• Increased melanin concentrating hormone receptor type I in the human hypothalamic infundibular nucleus in cachexia [19].

Associations of MCHR1 with chemical compounds

• Using HEK293 cells stably expressing MCHR1, we demonstrate that MCH, acting through MCHR1, antagonizes the action of forskolin, an adenylate cyclase activator that increases intracellular levels of cAMP [20].
• Both ATC0065 (IC(50) = 21.4 +/- 1.57 nM) and ATC0175 (IC(50) = 13.5 +/- 0.78 nM) showed potent antagonist activities at MCHR1, as assessed by MCH-increased guanosine 5'-O-(3-[(35)S]thio)phosphate ([(35)S]GTPgammaS) binding to human MCHR1 [21].
• Significant correlation was observed between the sucrose intake and the mRNA expression of MCH and MCHR1 in normal rats [22].
• For example, peptide 26 with d-Arg in place of L-Arg in position 6 and Asn in place of Gly in position 10, Ac-dArg(6)-cyclo(S-S)(Cys(7)-Met(8)-Leu(9)-Asn(10)-Arg(11)-Val(12)-Tyr(13)-Arg(14)-Pro(15)-Cys(16))-NH(2), was a potent hMCH-1R agonist (IC(50) = 0.5 nm, EC(50) = 47 nm) with more than 200-fold selectivity with respect to hMCH-2R [23].
• Arginine residue 155 in the second intracellular loop plays a critical role in rat melanin-concentrating hormone receptor 1 activation [24].

Physical interactions of MCHR1

• MIZIP was originally identified as a highly conserved zinc-finger protein from human brain interacting with the C-terminus of the melanin-concentrating hormone receptor 1 [25].
• The G protein-coupled receptor 24 encoded by GPR24 binds melanin-concentrating hormone (MCH) and has been implicated with feeding behavior, energy metabolism, and regulation of stress and mood [26].

Regulatory relationships of MCHR1

• [Ala(14)]-MCH was equipotent to native MCH in its ability to bind to and activate the wild-type MCH receptor, whereas [Ala(11)]-MCH displayed a 3000-fold reduction in binding affinity and a complete loss of measurable functional activity [27].
• DISCUSSION: These data indicate that potential therapeutics designed to act at the MCH receptor are unlikely to have altered effects in subpopulations that express variant forms of MCH-R1 or MCH-R2 [28].

Other interactions of MCHR1

• By comparison, the EC(50) and IC(50) values of salmon MCH and mammalian MCH at MCH-R1 were relatively similar [29].
• This receptor, named S643b, displays the greatest overall identity (32%) with the previously reported human SLC-1 receptor (MCH1) and to a lesser extent with the somatostatin receptor subtypes [18].
• For the melanin-concentrating hormone receptor the bulk of translocated beta-arrestin 2-GFP was maintained at concentrated foci close to, or at, the plasma membrane [30].
• LH release was stimulated by an agonist for MC5-R injected into the rPOA or mPOA; this was blocked by the MC5-R antagonist but not the MCH1-R antagonist [31].
• Compounds from this series exhibited considerable binding affinity (Ki = 1 nM) and functional activity at MCH-R1, acceptable CYP2D6 inhibition, and good rat brain exposure [32].

Analytical, diagnostic and therapeutic context of MCHR1

• Additionally, while female and male mice carrying a null mutation of the MCHR1 gene show comparable anxiolytic-like behavior on the open field, only female knockout mice exhibit antidepressant-like behavior, when tested on the forced swim and tail suspension tests [6].
• Site-directed mutagenesis of the rat MCHR1 cDNA at single or multiple combinations of the three potential glycosylation sites was used to examine the role of the putative carbohydrate chains on receptor activity [13].
• The discovery of these MCH receptors permitted the launch of a broad array of drug screening efforts and three MCH-1 receptor antagonists were identified to reduce food intake and body weight [33].
• Both MCH and MCHR1 are expressed in mouse and human islets and in clonal beta-cell lines as assessed using quantitative real-time PCR and immunohistochemistry [34].
• Molecular cloning and functional characterization of MCH2, a novel human MCH receptor [35].

References