1. The melanin-concentrating hormone: from the peptide to the gene
J L Nahon Crit Rev Neurobiol . 1994;8(4):221-62.
Melanin-concentrating hormone (MCH) is a cyclic peptide originally isolated from chum salmon pituitaries, then structurally characterized from rat hypothalami. In the fish, MCH induces melanin concentration within the melanophores and may inhibit ACTH secretion in vitro and under stressful conditions in vivo. In the rat, MCH modulates ACTH release in vivo and oxytocin secretion in vitro. However, on the basis of neuroanatomical features, that is, cell bodies almost exclusively confined to the lateral area of the hypothalamus and the zona incerta, while fibers are observed throughout whole rat or human brains, this peptide appears to participate as a neurotransmitter/neuromodulator in the control of goal-oriented behaviors and/or general arousal in mammals. The knowledge of structural and regulatory features of the MCH precursor, mRNA, and genes at the cellular and molecular levels has recently made great progress. (1) The cells expressing MCH and associated peptides have been defined conjointly using radioimmunoassay, immunocytochemistry, and in vitro and in vivo molecular hybridization techniques. (2) The organization of the precursor deduced from cDNA cloning has been established and led to the discovery of two novel putative peptides named NEI and NGE. (3) The regulation of MCH mRNA and peptide production has been explored during the course of development in rodent and human and under a variety of paradigms (neurogenic or osmotic stress, hormonal stimuli, etc.). (4) The structure of the MCH genes has been determined in salmon, rat, mouse, and human and revealed striking exon-intron organization differences between fish and mammals. Strong homology, with a likely functional implication, was found between salmon MCH mRNA and 7SL RNA, a structural RNA involved in protein translocation. Furthermore, a variant gene that may encode slightly different MCH was found exclusively in primates. (5) Chromosomal assignment of the authentic and variant MCH genes in rat and human indicates that these genes may be good candidates involved in neurodegenerative or psychiatric disorders. Based on the framework of these studies, a working model of MCH regulation/function in mammalian brain is finally proposed.
2. The distribution of melanin-concentrating hormone-like immunoreactivity in the central nervous system of rat, guinea-pig, pig and man
M A Ghatei, P W Burnet, J M Polak, S Lacoumenta, S R Bloom, N Zamir, J M Burrin, K Sekiya Neuroscience . 1988 Jun;25(3):925-30. doi: 10.1016/0306-4522(88)90046-2.
The distribution of melanin-concentrating hormone-like immunoreactivity was investigated by radioimmunoassay in the CNS of rat, guinea-pig, pig and man. Highest concentrations of melanin-concentrating hormone-like immunoreactivity were found in the hypothalamus of all the species: rat 204.4 +/- 14.9; guinea-pig 159.5 +/- 23.3; pig 10.9 +/- 4.5 and man 80.1 +/- 19.1 pmol/g. Gel chromatographic analysis of hypothalamic extracts showed five immunoreactive peaks of melanin-concentrating hormone-like immunoreactivity in the rat and pig and six in the guinea-pig and man. High-performance liquid chromatography analysis of hypothalamic extracts showed five immunoreactive peaks in rat, guinea-pig, pig and four in man. However, these peaks appeared at different retention times from that of the single peak of salmon melanin-concentrating hormone. Examination of subcellular fractions of whole rat brain showed that most of the melanin-concentrating hormone-like immunoreactivity is found in the synaptosome fraction. Stimulation of melanin-concentrating hormone-like immunoreactivity release from rat hypothalamic slices revealed that potassium in the presence of calcium stimulated melanin-concentrating hormone-like immunoreactivity release. These findings suggest that mammalian melanin-concentrating hormone-like immunoreactivity has a different amino acid sequence from salmon melanin-concentrating hormone and may exist in multiple molecular forms. It is possible that melanin-concentrating hormone may play a role as a neurotransmitter or modulator in the mammalian CNS.
3. Identification of melanin-concentrating hormone receptor and its impact on drug discovery
Yumiko Saito, Kei Maruyama J Exp Zool A Comp Exp Biol . 2006 Sep 1;305(9):761-8. doi: 10.1002/jez.a.311.
The neuropeptide melanin-concentrating hormone (MCH) was originally isolated from the pituitary of salmon, in which it causes skin paling. MCH is also found abundantly in mammalian neurons, and has been detected in the lateral hypothalamus and zona incerta, brain regions that are at the center of feeding behavior. Acute central administration of MCH leads to a rapid and significant increase in food intake, while MCH expression changes in states of altered energy balance, such as fasting and obesity. Furthermore, MCH knockout mice tend toward hypophagia and leanness. In 1999, we and four other groups identified an orphan G-protein-coupled receptor (GPCR) as a specific receptor for MCH (MCH-1 receptor). Although a second MCH receptor (MCH-2 receptor) was isolated in humans, it was found to be non-functional or encode a non-functional pseudogene in non-human species, including rodents. 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. Interestingly, some antagonists unexpectedly produced evidence that blockade of these receptors has antidepressant and anxiolytic activities. The expressions of the MCH receptors, which have been implicated in regulating emotion, stress and motivation, make MCH an excellent candidate for integrating the various homeostatic stimuli necessary for maintaining the proper conditions of energy metabolism and other physiological functions. Finally, the speed at which MCH receptor studies have been undertaken exemplifies the impact that this deorphanized GPCR will have on setting the stage for more detailed physiological studies.
