Melanin-Concentrating Hormone Receptors

Melanin concentrating hormone (MCH) is a nonadecapeptide with a highly conserved amino acid sequence that is found in a variety of species from fish to mammals. Originally isolated from chum salmon pituitary, MCH changes the distribution of melanosomes by stimulating their aggregation, and functions as a physiological antagonist of α-melanocyte stimulating hormone (α-MSH). In mammals, MCH is synthesized in the central nervous system, specifically in the magnocellular cell bodies of the lateral hypothalamus and zona incerta. The cell bodies of MCH-containing neurons project widely to the cerebral cortex, amygdala, nucleus accumbens, olfactory tubercle and brainstem nuclei. In mammals, MCH is synthesized from a prepropeptide, encoded by the Pmch gene, from which neuropeptide E-I and neuropeptide G-E are also derived. Alternative splicing of Pmch also gives rise to additional peptides such as MCH-gene-overprinted-polypeptide (MGOP).

The role of MCH in mammals was elucidated when, using RT-PCR differential display, the expression of the Pmch gene was shown to be increased in ob/ob mice. These mice provide a genetic model of obesity and suggested a role for MCH in energy homeostasis. The central administration of MCH evokes feeding behavior, and increased expression of Pmch is observed in fasted animals. Conversely, feeding as well as leptin treatment to normal and ob/ob mice suppresses the expression of Pmch. Further studies of the phenotype of mice with targeted gene deletion of Pmch confirmed the initial observations and showed a 25% reduction in body weight, by reduction in feeding and increased energy expenditure. The transgenic over expression of Pmch caused an increased propensity to obesity by high fat diet, hyperinsulinemia and insulin resistance.

The effects of MCH are mediated by two G protein-coupled receptors, referred to as MCH1 and MCH2. The MCH1 receptor was discovered using a reverse pharmacology approach in which MCH was found to increase either intracellular calcium or adenylyl cyclase inhibition in cells expressing the then orphan receptor SLC-1 (or GPR24). MCH1 couples to multiple G proteins, activating the release of intracellular calcium through coupling to Gq and suppressing forskolin activation of adenylyl cyclase by coupling to Gi/o in a pertussis toxin-sensitive manner. The expression of MCH1 is most abundant in brain (cortex, basal ganglia, hypothalamus and brainstem) with weak expression in muscle, eye, tongue and adipose tissue. The targeted deletion of the gene encoding the MCH1 receptor in mice yields a lean phenotype with reduced fat mass, increased activity and resistance to diet-induced obesity, suggesting that MCH1 mediates the effects of MCH on energy homeostasis in rodents. In line with this evidence selective, peptidergic and small molecule, MCH1 antagonists such as T-226296 and SNAP7941 have also been found to inhibit the feeding response evoked by MCH, and to reduce body weight after chronic administration to rats with diet-induced-obesity. In addition, SNAP7941, ATC0065 and ATC0175 were also found to be effective in animal models of anxiety and depression, uncovering a role of MCH in the regulation of mood and emotion, with implications for the use of MCH1 antagonists in the treatment of affective disorders.

The MCH2 receptor, which is also activated by MCH and coupled to Gq, was discovered based on its homology to MCH1. With a predominant CNS distribution, MCH2 is not expressed in rodents and has only been found in dog, ferrets, rhesus monkeys and humans. The current lack of pharmacological tools for MCH2 and the species-specific expression of this receptor have hindered the assessment of its functional role.

 

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

 

Currently Accepted Name MCH1 MCH2
Previous Names MCH1R
SLC1
MCHR1
MGC32129
GPR24
GPR145
SLT
MCH2R
MCHR2
Structural Information 353 aa (human) 340 aa (human)
Preferred Endogenous Peptide Melanin concentrating hormone (human, rat, mouse) Melanin concentrating hormone (human, rat, mouse)
Selective Peptide Agonists [D-Arg6,Asn10]Ac-hMCH(6-16)-NH2a
[D-Arg6,Gln10]Ac-hMCH(6-16)-NH2a
Not Known
Selective Peptide Antagonists Compound Bb Not Known
Selective Non-Peptide Antagonists SNAP7941
T-226296
ATC0065
ATC0175 (A3355)
Not Known
Radioligand of Choice [125I]-S36057
[125I]-[Phe13,3-iodo-Tyr19]MCH
[125I]-S36057
[125I]-[Phe13,3-iodo-Tyr19]MCH
Tissue Expression CNS (nucleus accumbens, cerebral cortex, amydgdala, hippocampus, hypothalamus, striatum, locus coeruleus and medulla oblongata), pituitary, muscle, eye, tongue
and adipose tissue
CNS (cerebral cortex, nucleus, accumbens, amygdala, hippocampus, adipose tissue, intestine, spleen, prostate)
Physiological Function Energy homeostasis, neuroendocrine regulation, modulation of mood and appetitive behaviors Not Known
Disease Relevance Obesity, depressive disorders and anxiety Not Known

 

Footnotes

a) see Bednarek, M.A., et al, J. Biol. Chem., 277, 13821-13826 (2002).

b) see Bednarek, M.A., et al, Biochemistry, 41, 6383-6390 (2002).

 

Abbreviations

ATC0065: N2-[cis-4-({2-[4-Bromo-2-(trifl uoromethoxy)phenyl]ethyl}amino)cyclohexyl]-N4, N4-dimethylquinazoline-2,4-diamine dihydrochloride
ATC0175: [N-(cis-4-{[4-(Dimethylamino)quinazolin-2-yl]amino}cyclohexyl)-3,4-difl uorobenzamide hydrochloride
SNAP 7941: (+)-Methyl (4S)-3-{[(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)amino]carbonyl}-4-(3,4-difl uorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4,-tetrahydro-5-pyrimidinecarboxylate hydrochloride
T-226296: (-)-N-[6-(Dimethylamino)-methyl]-5,6,7,8-tetrahydro-2-naphthalenyl]-4'-fl uoro[1,1'-biphenyl]-4-carboxamide

 

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References