Characterization of [Phe13, Tyr19]-MCH analog binding activity to the MCH receptor

Kokkotou, Efi; Mastaitis, Jason; Qu, Daqing; Hoersch, Dieter; Slieker, Lawrence J.; Bonter, K.; Tritos, Nicholas A.; Maratos–Flier, Eleftheria

doi:10.1054/npep.2000.0821

Cited by 18 publications

(12 citation statements)

References 25 publications

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“…This may therefore imply the existence of still further subtypes of the MCH receptor. However, recent studies (33) have demonstrated that the specific binding to some of these cell lines is unlikely to be caused by the presence of a receptor involved in signal transduction, because binding is largely localized to microsomal and not plasma membranes, and the internalization kinetics are not typical of a receptor-mediated event.…”

Section: Discussionmentioning

confidence: 99%

Molecular Cloning and Functional Characterization of MCH2, a Novel Human MCH Receptor

Hill¹,

Duckworth²,

Murdock³

et al. 2001

Journal of Biological Chemistry

219

144

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Melanin-concentrating hormone (MCH) is involved in the regulation of feeding and energy homeostasis. Recently, a 353-amino acid splice variant form of the human orphan receptor SLC-1 (1) (hereafter referred to as MCH 1 ) was identified as an MCH receptor. This report describes the cloning and functional characterization of a novel second human MCH receptor, which we designate MCH 2 , initially identified in a genomic survey sequence as being homologous to MCH 1 receptors. Using this sequence, a full-length cDNA was generated with an open reading frame of 1023 base pairs, encoding a polypeptide of 340 amino acids, with 38% identity to MCH 1 and with many of the structural features conserved in G protein-coupled receptors. This newly discovered receptor belongs to class 1 (rhodopsin-like) of the G protein-coupled receptor superfamily. HEK293 cells transfected with MCH 2 receptors responded to nanomolar concentrations of MCH with an increase in intracellular Ca 2؉ levels and increased cellular extrusion of protons. In addition, fluorescently labeled MCH bound with nanomolar affinity to these cells. The tissue localization of MCH 2 receptor mRNA, as determined by quantitative reverse transcription-polymerase chain reaction, was similar to that of MCH 1 in that both receptors are expressed predominantly in the brain. The discovery of a novel MCH receptor represents a new potential drug target and will allow the further elucidation of MCH-mediated responses. Melanin-concentrating hormone (MCH)1 is a cyclic neuropeptide that was first discovered in teleost fish, in which it acts as a skin color-regulating hormone (2). In rodents its tissue distribution in the perikarya of the lateral hypothalamus and the zona incerta suggests that MCH may be involved in a variety of behavioral responses (3). Similar tissue distributions have been reported in both bird (4) and monkey (5). Reports implicating MCH in the regulation of feeding behavior show that increased food intake occurs after direct administration of MCH into the brain (6) and that MCH is up-regulated after fasting and in obese leptin-deficient mice (7). There are also reports that suggest MCH may be involved in aggressive behavior, anxiety, and reproductive function (8, 9).Recently, several groups independently identified a 353-amino acid splice variant of the orphan G protein-coupled receptor (GPCR) SLC-1 (1) as an MCH receptor (10 -14). In view of the findings of the current study, we propose that this form of SLC-1 be hereafter referred to as MCH 1 . Southern blot and related studies have indicated the absence of additional MCH receptor subtypes that closely resemble MCH 1 at the DNA level (3, 10, 15). However, because degeneracy in receptor-ligand pairings throughout the GPCR superfamily is common, we reasoned that other MCH receptors with low homology to the MCH 1 receptor may exist. This suggestion is supported by reports of pharmacological differences between the MCH 1 receptor and MCH binding sites in various cell lines and tissues (10).Sequencing of the human...

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Section: Discussionmentioning

confidence: 99%

Molecular Cloning and Functional Characterization of MCH2, a Novel Human MCH Receptor

Hill¹,

Duckworth²,

Murdock³

et al. 2001

Journal of Biological Chemistry

219

144

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“…Locomotion is typically regulated by the dopamine system, particularly the nucleus accumbens. MCH neurons are known to project from the lateral hypothalamus to both accumbens and caudate putamen, and both of these areas are rich in expression of MCHR-1 (19,29). It is possible that MCH plays a role in regulating dopaminergic systems and that mice without MCH have altered dopaminergic tone.…”

Section: Mchmentioning

confidence: 99%

Mice with MCH ablation resist diet-induced obesity through strain-specific mechanisms

Kokkotou

Jeon²,

Wang

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

138

102

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Genetics and environment contribute to the development of obesity, in both humans and rodents. However, the potential interaction between genes important in energy balance, strain background, and dietary environment has been only minimally explored. We investigated the effects of genetic ablation of melanin-concentrating hormone (MCH), a neuropeptide with a key role in energy balance, with chow and a high-fat diet (HFD) in two different mouse strains, one obesity-prone (C57BL/6) and the other obesity-resistant (129). Substantial differences were seen in wild-type (WT) animals of different strains. 129 animals had significantly lower levels of spontaneous locomotor activity than C57BL/6; however, 129 mice gained less weight on both chow and HFD. In both strains, deletion of MCH led to attenuated weight gain compared with WT counterparts, an effect secondary to increased energy expenditure. In both strains, feeding a HFD led to further increases in energy expenditure in both WT and MCH-KO mice; however, this increase was more pronounced in 129 mice. In addition, mice lacking MCH have a phenotype of increased locomotor activity, an effect also seen in both strains. The relative increase in activity in MCH(-/-) mice is modest in animals fed chow but increases substantially when animals are placed on HFD. These studies reinforce the important role of MCH in energy homeostasis and indicate that MCH is a plausible target for antiobesity therapy.

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“…ϩ RNA (CLONTECH) was reversed-transcribed with oligo (dT) [12][13][14][15][16][17][18] using reverse Transcriptase Superscript II (Life Technologies, Inc.). First strand cDNA (corresponding to 1 g of total RNA) was subjected to 35 cycles of amplification using the forward primer 5Ј-GAGACCCAAGCTTCTGGATGGACCTGGAAGCCT-3Ј and the reverse primer 5Ј-GATGACGCGGCCGCTCAGGTGCCTTTGCTTTCTG-3Ј (33).…”

Section: Cloning Of the Human Mch Receptor (Slc-1)-human Brain Poly(a)mentioning

confidence: 99%

Structure-Activity Relationship Studies of Melanin-concentrating Hormone (MCH)-related Peptide Ligands at SLC-1, the Human MCH Receptor

Audinot

Beauverger

Lahaye

et al. 2001

Journal of Biological Chemistry

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Melanin-concentrating hormone (MCH) is a cyclic nona- Melanin-concentrating hormone (MCH)1 has been initially described in fish as a heptadecapeptide (Asp-Thr-Met-Arg-CysMet-Val-Gly-Arg-Val-Tyr-Arg-Pro-Cys-Trp-Glu-Val (1)). Its structure was relatively conserved throughout evolution, although in mammals the sequence of MCH is a nonadecapeptide with differences mainly in the N terminus (Asp-Phe-Asp-MetLeu-Arg-Cys-Met-Leu-Gly-Arg-Val-Tyr-Arg-Pro-Cys-Trp-GlnVal (2)). In rodents, there are now several lines of evidence for the involvement of MCH in the central regulation of feeding behavior as reviewed by Tritos and Maratos-Flier (3). The MCH peptide and its receptor are expressed in the hypothalamus, a region involved in energy balance and food intake (4 -7). In this particular brain area, MCH mRNA is overexpressed and up-regulated during fasting in ob/ob mice as well as in rats (8, 9). Intra-cerebroventricular injections of MCH promote feeding in mice and rats (9 -12). Finally, transgenic mice lacking the MCH gene are lean and hypophagic (13). Interestingly, in peripheral tissues, MCH also stimulates the release of leptin from isolated rat adipocytes (14). The lack of suitable binding conditions, mainly due to the hydrophobic and sticky nature of MCH itself or derivatives (15, 16), was probably a limitation for expression cloning of the receptor. The MCH receptor was nevertheless recently identified by several groups using reverse pharmacology (17-21). The MCH function was assigned to the previously described orphan receptor SLC-1 (22, 23), using inhibition of forskolin-stimulated cAMP production and induction of calcium rise.Receptor cloning and association of functional tests open the way to the search for pharmacological tools, especially receptor antagonists that are needed to study receptor functions. One of the possible strategies to this goal is the chemical modification of the natural peptide including peptide shortening, amino acid substitution, and conformation restriction with the help of structure-activity relationships and modeling studies toward optimized nonpeptide ligands. Such a strategy has been successful for the design of subtype-specific antagonists of neuropeptide Y receptors (24 -27).In the case of MCH, only two sets of data have been published on the pharmacological action and binding affinity of MCH analogues in vitro. A first series of experiments with fish MCH on fish, frog, or other batrachian skin assays were reported (28 -32), showing that fish MCH could be shortened at * This work was supported by a a Convention CIFRE between the Association Nationale de la Recherche Technique, the Institut de Recherches SERVIER and the Centre National de la Recherche Scientifique (to T. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.*

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Characterization of [Phe13, Tyr19]-MCH analog binding activity to the MCH receptor

Cited by 18 publications

References 25 publications

Molecular Cloning and Functional Characterization of MCH2, a Novel Human MCH Receptor

Molecular Cloning and Functional Characterization of MCH2, a Novel Human MCH Receptor

Mice with MCH ablation resist diet-induced obesity through strain-specific mechanisms

Structure-Activity Relationship Studies of Melanin-concentrating Hormone (MCH)-related Peptide Ligands at SLC-1, the Human MCH Receptor

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