MCHR1

Official Full Name

melanin concentrating hormone receptor 1

Organism

Homo sapiens

GeneID

2847

Background

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]

Synonyms

SLC1; GPR24; MCH1R; SLC-1; MCH-1R;

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Detailed Information

Melanin-concentrating hormone (MCH) is a cyclic amino acid containing 19 amino acids. It was first discovered in teleost fish and has the effect of regulating the color change of teleost fish. Both endogenous MCH receptors MCHR1 and MCHR2 are G-protein coupled receptors. MCHR1 is expressed in the hypothalamus of rodents and advanced mammals. MCHR1 is a G protein-coupled receptor that is highly conserved in rats, mice and humans. In addition, MCHR1 is mainly expressed in the brain, especially in the hippocampus, olfactory region and medial nucleus accumbens, indicating that MCHR1 is involved in the learning and enhancement of olfaction and is associated with feeding regulation. Studies have shown that animals lacking the MCHR1 gene have decreased body mass and sugar content, increased activity, and are not susceptible to obesity induced by a high-fat diet. In addition to the central role, MCHR1 is also present in peripheral tissues such as fat, small intestine, and pancreas, and plays an important role in the metabolism of the body.

Figure 1. Structure of MCH and MCHR1.（Philippe, et al.2017）

MCHR1 and Obesity

MCHR1 was confirmed in 1999 to regulate diet and energy balance. MCH acts primarily by binding to the MCHR1 receptor. MCHR1 agonists can promote the expression of NPY mRNA in the arcuate nucleus of the hypothalamus, and have a significant effect on the expression of energy balance related genes in the brain and the regulation of animal energy balance. The level of MCHR1 in hereditary obese rats is higher. MCHR1 extracts increased leptin and insulin levels, and is slim, which can significantly resist obesity characterized by excess appetite, hyperactivity and hypermetabolism. Studies have shown that MCHR1 coupled with G protein activates the mitogen-activated protein kinase (MAPK) pathway, which transmits extracellular signals into the cell and participates in cell differentiation.

MCHR1 is an important regulator of MCH's role in energy balance. The study found that MCHR1 is not only highly expressed in the central system, but also in white adipose tissue, pancreas and small intestine. Compared with normal wild mice, MCHR1 knockout mice lost weight and reduced fat accumulation. Therefore, MCHR1 has become a new target for weight loss drug research. Studies suggest that although MCHR1 exerts anti-obesity effects primarily through the central system, direct action on peripheral tissues or cells may also have positive implications. At present, scholars believe that the increase in the number of fat cells and the increase in volume are the key factors leading to obesity, and the changes in fat cells are closely related to the differentiation of preadipocytes. Neuropharmacology combined with behavioral experiments found that activation of MCHR1 significantly promoted food intake, suggesting that high-fat diet can further promote the body's energy imbalance by up-regulating MCHR1 mRNA in peripheral adipose tissue.

MCHR1 Antagonist

MCH and MCHR1 antagonists have been extensively studied, and many MCHR1 antagonists with high selectivity, high activity and good pharmacokinetic properties have been discovered and confirmed by various research methods. Cardiovascular safety factors associated with hERG channels caused by partial MCHR1 antagonists are worth considering. MCHR1 antagonists can effectively regulate energy balance and food intake, inhibit the increase of food intake and body mass of rodent animals and humans, and become the focus of anti-obesity drug research. Studies on the molecular model and the intercalation of receptor ligands confirmed that the two amino acid residues of MCHR1 (Gln5.42 and Gln6.55) play a very important role in interacting with antagonists.

References:

Philippe, C., & Mitterhauser, M. (2017). The Potential Role of the MCHR1 in Diagnostic Imaging: Facts and Trends. In Melanin. InTech.
Johansson, A. (2016). Evolution of physicochemical properties of melanin concentrating hormone receptor 1 (MCHr1) antagonists. Bioorganic & medicinal chemistry letters, 26(19), 4559-4564.
Golden, M., Legg, D., Milne, D., Bharadwaj M, A., Deepthi, K., Gopal, M., ... & Sharma, P. (2016). The Development of a Manufacturing Route to an MCHr1 Antagonist. Organic Process Research & Development, 20(3), 675-682.

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