Identification and Pharmacological Characterization of a Novel Human Melanin-concentrating Hormone Receptor, MCH-R2

Wang, Suke; Behan, Jiang; O’Neill, Kim; Weig, Blair; Fried, Steven D.E.; Laz, Thomas M.; Bayne, Marvin L.; Gustafson, Eric L.; Hawes, Brian E.

doi:10.1074/jbc.m102601200

Cited by 101 publications

(58 citation statements)

References 29 publications

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“…The distribution of MCH-1 receptor in the rat brain and spinal cord (Hervieu et al, 2000) overlaps the areas exhibiting MCH immunoreactivity (Bittencourt and Elias, 1998). A second MCH receptor, called the MCH-2 receptor, has also been identified (Hill et al, 2001;Mori et al, 2001;Rodriguez et al, 2001;Sailer et al, 2001;Songzhu et al, 2001;Wang et al, 2001). Non-primate species, including the rat, do not possess a functional MCH-2 receptor .…”

Section: Introductionmentioning

confidence: 99%

Microinjections of melanin concentrating hormone into the nucleus tractus solitarius of the rat elicit depressor and bradycardic responses

et al. 2007

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The presence of melanin-concentrating hormone (MCH) containing processes, projecting from the lateral hypothalamus to the medial nucleus tractus solitarius (mNTS), has been reported in the rat. It was hypothesized that MCH acting within the mNTS may modulate the central regulation of cardiovascular function. This hypothesis was tested in urethane-anesthetized, artificially ventilated, adult male Wistar rats. Microinjections (100 nl) of MCH (0.25, 0.5, 0.75, and 1 mM) into the mNTS of anesthetized rats elicited decreases in mean arterial pressure (20.4 ± 1.6, 50.7 ± 3.3, 35.7 ± 2.8 and 30.0 ± 2.6 mmHg, respectively). The decreases in heart rate in response to these concentrations of MCH were 40.0 ± 8.7, 90.0 ± 13.0, 48.0 ± 7.3 and 48.0 ± 8.0 beats/min, respectively. Maximum cardiovascular responses were elicited by a 0.5 mM concentration of MCH. Cardiovascular responses to MCH were similar in unanesthetized mid-collicular decerebrate rats. Control microinjections of normal saline (100 nl) did not elicit any cardiovascular response. Ipsilateral or bilateral vagotomy significantly attenuated MCH-induced bradycardia. Prior microinjections of PMC-3881-PI (2 mM; MCH-1 receptor antagonist) into the mNTS blocked the cardiovascular responses to microinjections of MCH. Microinjection of MCH (0.5 mM) into the mNTS decreased efferent greater splanchnic nerve activity. Direct application of MCH (0.5 mM; 4 nl) to barosensitive NTS neurons increased their firing rate. These results indicate that: 1) MCH microinjections into the mNTS activate MCH-1 receptors and excite barosensitive NTS neurons, causing a decrease in efferent sympathetic activity and blood pressure, and 2) MCH-induced bradycardia is mediated via the activation of the vagus nerves.

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Section: Introductionmentioning

confidence: 99%

Microinjections of melanin concentrating hormone into the nucleus tractus solitarius of the rat elicit depressor and bradycardic responses

et al. 2007

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“…Subsequently, a second high-affinity MCH receptor (MCH2R) with moderate amino acid identity to MCH1R was identified in humans (11)(12)(13)(14)(15). Both receptors are highly selective for MCH and are not activated by NEI, neuropeptide GE, or MCH-gene-overprinted-polypeptide (13,16,17); however, in vivo validation for these receptors is still lacking.…”

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Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism

Marsh

Weingarth²,

Novi³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

536

371

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Melanin-concentrating hormone (MCH) is a cyclic 19-aa hypothalamic neuropeptide derived from a larger prohormone precursor of MCH (Pmch), which also encodes neuropeptide EI (NEI) and neuropeptide GE (NGE). Pmch-deficient (PmchM elanin-concentrating hormone (MCH) is expressed in the central nervous system predominantly in neurons in the lateral hypothalamus and zona incerta, which project broadly throughout the brain (1, 2). MCH mRNA levels are increased in response to fasting and are elevated in leptin-deficient ob͞ob mice relative to control mice (3), suggesting that leptin negatively regulates MCH. Rodent pharmacology further supports a role for MCH in the control of energy homeostasis, as centrally administered MCH stimulates food intake in rats (3, 4).In addition to MCH, prohormone precursor of MCH (Pmch) also encodes neuropeptide EI (NEI) and neuropeptide GE (NGE) (5) and may potentially give rise to an alternative splice variant termed MCH-gene-overprinted-polypeptide (MGOP; ref. 6), as well as encode a portion of the recently identified antisense-RNA-overlapping-MCH (AROM; ref. 7). Two recently described mouse genetic models further implicate MCH in the regulation of energy homeostasis. Pmch Ϫ/Ϫ mice are lean, hypophagic, and have an increased metabolic rate (8). In contrast, transgenic mice overexpressing Pmch develop mild obesity, are hyperphagic, and become insulin-resistant (9). As both these models represent genetic manipulations of Pmch, one must consider the possibility that in addition to alterations in MCH, changes in the levels of NEI and NGE, as well as potentially MGOP and AROM, may also contribute to the phenotypes of these models.The MCH 1 receptor (MCH1R) was initially identified as an orphan G protein-coupled receptor that bound MCH with high affinity (10). Subsequently, a second high-affinity MCH receptor (MCH2R) with moderate amino acid identity to MCH1R was identified in humans (11-15). Both receptors are highly selective for MCH and are not activated by NEI, neuropeptide GE, or MCH-gene-overprinted-polypeptide (13, 16, 17); however, in vivo validation for these receptors is still lacking. We generated Mch1r Ϫ/Ϫ mice to evaluate the physiological function of MCH1R, and to determine whether it is involved in mediating the effects of MCH on energy homeostasis. Additionally, we hoped to gain insight into what aspects of the Pmch Ϫ/Ϫ and Pmch overexpressing phenotypes are likely attributed to MCH. Materials and MethodsAnimal Care and Maintenance. All animal protocols used in these studies were approved by the Merck Research Laboratories Institutional Animal Care and Use Committee in Rahway, NJ. We housed mice in microisolator cages (Lab Products, Maywood, NJ) in a barrier facility with an air shower entrance or in a specific pathogen-free facility. Mice were maintained on either regular chow [Teklad (Madison, WI) 7012: 14.8% kcal from fat; Harlan Teklad], a moderate-fat diet (D12266B: 32% kcal from fat; Research Diets, New Brunswick, NJ), or a high-fat diet (Teklad 97070: 60% kcal from fat)...

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“…This polypeptide was thus renamed the MCH-1 receptor. A second MCH receptor (MCH-2 receptor) has also been identified (7)(8)(9)(10)(11), and there is some evidence of an MCH binding site that is distinct from these two receptors (12).…”

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Periplakin Interferes with G Protein Activation by the Melanin-concentrating Hormone Receptor-1 by Binding to the Proximal Segment of the Receptor C-terminal Tail

Murdoch

Feng

Bächner

et al. 2005

Journal of Biological Chemistry

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The orexigenic cyclic 19 amino acid peptide melanin-concentrating hormone (MCH) 1 (1) is the natural ligand for the G protein-coupled receptor (GPCR) originally designated SLC-1 (also called GPR24 in some studies) because of its relatedness to the receptors for somatostatin (2-6). This polypeptide was thus renamed the MCH-1 receptor. A second MCH receptor (MCH-2 receptor) has also been identified (7-11), and there is some evidence of an MCH binding site that is distinct from these two receptors (12).Even before identification of the MCH receptors a clear role for MCH in feeding and energy balance and homeostasis had been established (1). A solid body of genetic and pharmacological evidence now supports a role for MCH and the MCH-1 receptor in the modulation of food intake and energy expenditure. Key data derive from the genetic ablation of both MCH (13) and the MCH-1 receptor (14, 15) in mice. These alterations produced animals that were both lean and resistant to dietinduced obesity. Mice lacking the MCH-1 receptor have been reported to be hyperphagic (14, 15) but to be both hyperactive and to have altered metabolism, and this may explain the apparent paradox of being resistant to obesity but eating more. Studies also indicate that acute and chronic administration of MCH enhances food intake and body weight (16) and that overexpression of MCH in transgenic mice leads to obesity and insulin resistance (17). A role for the MCH-2 receptor in these effects is unlikely because genetic evidence indicates that mice do not express a functional form of this receptor (18). Furthermore, the distribution of the MCH-1 receptor in the central nervous system (19) also suggests that antagonists at the MCH-1 receptor might provide a treatment for obesity (for review, see Refs. 20 and 21). High throughput screening efforts have led to the identification of small molecule MCH-1 receptor antagonists with diverse structural features and drug-like properties. In vivo results with two of these antagonists indicate efficacy in several animal models of body weight regulation and feeding behavior (21). At least when expressed in

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Identification and Pharmacological Characterization of a Novel Human Melanin-concentrating Hormone Receptor, MCH-R2

Cited by 101 publications

References 29 publications

Microinjections of melanin concentrating hormone into the nucleus tractus solitarius of the rat elicit depressor and bradycardic responses

Microinjections of melanin concentrating hormone into the nucleus tractus solitarius of the rat elicit depressor and bradycardic responses

Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism

Periplakin Interferes with G Protein Activation by the Melanin-concentrating Hormone Receptor-1 by Binding to the Proximal Segment of the Receptor C-terminal Tail

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