Isolation and Identification of Melanin-Concentrating Hormone as the Endogenous Ligand of the SLC-1 Receptor

Shimomura, Yukio; Mori, Masataka; Sugo, Tsukasa; Ishibashi, Yoshihiro; Abe, Michiko; Kurokawa, Tsutomu; Onda, Haruo; Nishimura, Osamu; Sumino, Yasuhiro; Fujino, Masahiko

doi:10.1006/bbrc.1999.1104

Cited by 166 publications

(87 citation statements)

References 20 publications

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“…MCH has been identified as a natural ligand for an orphan G-protein coupled receptor, called SLC-1 receptor because of its sequence similarity with somatostatin receptor (Bachner et al, 1999;Chambers et al, 1999;Lembo et al, 1999;Saito et al, 1999;Saito et al, 2000;Shimomura et al, 1999). The SLC-1 receptor, re-named as the MCH-1 receptor, has been cloned in the rat and mouse Lakaye et al, 1998).…”

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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“…However, MCH fibers project in many areas throughout the CNS (6,9), indicating that the MCH system may have a broad range of physiological roles. In rodents, MCH is known to interact with one G protein-coupled receptor, MCH1R (14)(15)(16)(17)(18). MCH1R is expressed in many brain regions (9), and the NAcSh has one of the highest MCH1R expression levels.…”

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The melanin-concentrating hormone system modulates cocaine reward

Chung

Hopf

Nagasaki

et al. 2009

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

129

140

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Drug addiction is mediated by complex neuronal processes that converge on the shell of the nucleus accumbens (NAcSh). The NAcSh receives inputs from the lateral hypothalamus (LH), where selfstimulation can be induced. Melanin-concentrating hormone (MCH) is produced mainly in the LH, and its receptor (MCH1R) is highly expressed in the NAcSh. We found that, in the NAcSh, MCH1R is coexpressed with dopamine receptors (D1R and D2R), and that MCH increases spike firing when both D1R and D2R are activated. Also, injecting MCH potentiates cocaine-induced hyperactivity in mice. Mice lacking MCH1R exhibit decreased cocaine-induced conditioned place preference, as well as cocaine sensitization. Using a specific MCH1R antagonist, we further show that acute blockade of the MCH system not only reduces cocaine self-administration, but also attenuates cue-and cocaine-induced reinstatement. Thus, the MCH system has an important modulatory role in cocaine reward and reinforcement by potentiating the dopaminergic system in the NAcSh, which may provide a new rationale for treating cocaine addiction.T he shell of the nucleus accumbens (NAcSh) is known to be an important center for reward and motivation. It is a major terminal area of the mesolimbic dopamingergic system, which projects from the ventral tegmental area (VTA) (1). The NAcSh neurons express both dopamine D1 and D2 receptors, which have opposite effects on cAMP-dependent signaling; however, motivated behaviors require concomitant D1 and D2 receptor signaling in the NAcSh (2). The NAcSh receives inputs from different brain areas, in particular, from the lateral hypothalamus (LH) (3). The importance of the LH in reward and motivation has been shown by Olds (4), who discovered that electrical activation of the LH induced an extraordinarily intense self-stimulation response in rats. However, the transmitter(s) responsible for this action have not been established definitively. We now know of 2 neuropeptides that are uniquely synthesized in the LH: the orexins/hypocretins (5), and melanin-concentrating hormone (MCH) (6-8). The orexin/ hypocretin neurons do not project prominently to the NAcSh, whereas the MCH neurons do (9). This data suggested to us that the MCH system may regulate the activities of the NAcSh neurons to influence reward.MCH is a cyclic, 19-amino acid peptide originally isolated from salmon pituitary as a melanophore-concentrating factor (10). It is also present in rats and humans (11,12), where it is viewed as important in regulating nutritional homeostasis (8, 13). In mammals, MCH is expressed predominantly centrally, and occurs only in 2 nuclei: the perikarya of the LH area (LHA), and the zona incerta (ZI). However, MCH fibers project in many areas throughout the CNS (6, 9), indicating that the MCH system may have a broad range of physiological roles. In rodents, MCH is known to interact with one G protein-coupled receptor, MCH1R (14-18). MCH1R is expressed in many brain regions (9), and the NAcSh has one of the highest MCH1R expression levels. Indeed, the ...

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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)(3)(4)(5)(6). This polypeptide was thus renamed the MCH-1 receptor.…”

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“…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 heterologous cell lines, the MCH-1 receptor is able to regulate signal transduction through both G i -and G q -coupled pathways (2)(3)(4)(5)(6). Despite this, little is known about the regulation of this receptor.…”

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confidence: 99%

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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Isolation and Identification of Melanin-Concentrating Hormone as the Endogenous Ligand of the SLC-1 Receptor

Cited by 166 publications

References 20 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

The melanin-concentrating hormone system modulates cocaine reward

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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