Role of third intracellular loop of the melanocortin 4 receptor in the regulation of constitutive activity

Kim, Do Hun; Shin, Seung Woo; Baik, Ja Hyun

doi:10.1016/j.bbrc.2007.10.170

Cited by 19 publications

(18 citation statements)

References 21 publications

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“…1). R165Q, G231S, and I269N were previously known to lead to partial loss of function (1,7,23,24), consistent with our findings. The frameshift mutation, D37stop, predicted termination of the protein prior to the ligand binding domains yet had some detectable activity with exposure to high concentrations of ligand.…”

Section: Resultssupporting

confidence: 92%

“…Pima population–specific z scores were calculated for each individual by subtracting the mean from the individual’s value and dividing by the SD. For comparison with reference values, BMI z scores also were calculated from the standards published by the National Center for Health Statistics of the Centers for Disease Control and Prevention (21) using the recommended equation for normalized z scores. The number of nondiabetic, nonpregnant study exams with data for height and weight ranged from 1 to 17 in 5,977 individuals for a total of 26,385 examinations between 1965 and 2007 (Tables 1 and 2).…”

Section: Methodsmentioning

confidence: 99%

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Greater Impact of Melanocortin-4 Receptor Deficiency on Rates of Growth and Risk of Type 2 Diabetes During Childhood Compared With Adulthood in Pima Indians

et al. 2011

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Features of melanocortin-4 receptor (MC4R) deficiency have been observed to be more pronounced in childhood. Longitudinal data from a population-based study were used to separate the phenotypic effects of MC4R deficiency during childhood and adulthood. The MC4R exon was sequenced in 6,760 individuals of predominantly Pima Indian heritage, and discovered mutations were functionally assessed in vitro. Effects on BMI, height, and slope of BMI change were assessed during childhood (ages 5–20 years) and adulthood (ages 20–45 years). Six mutations affecting MC4R function, including three that may be private to Pima Indians, were found in 159 individuals (2.4%). The slope of BMI increase was greater in individuals carrying an MC4R mutation compared with noncarriers during childhood but not during adulthood. The final adult height obtained was higher in individuals with MC4R deficiency. There was an increased risk for developing type 2 diabetes in individuals with a defective MC4R during childhood and adulthood, but this was only independent of BMI in childhood. The greater rates of body mass accumulation and risk of type 2 diabetes before the age of 20 years in individuals with MC4R deficiency indicate that the effects of these mutations are more apparent during the active growth of childhood.

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Section: Resultssupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Greater Impact of Melanocortin-4 Receptor Deficiency on Rates of Growth and Risk of Type 2 Diabetes During Childhood Compared With Adulthood in Pima Indians

et al. 2011

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“…The core tetrapeptide of NDP-MSH (with both β-turn types d -Phe 7 -Arg 8 and His 6 - d -Phe 7 ) had been manually docked into the binding pocket of our MC4R model using Autodock 60 and refined with MOE 53 before the complete peptide was modeled in situ with Modeller9v5, 61 as described in Materials and Methods. The modeled proximity of the residues in the peptide to the receptor and the experimental data were examined and compared (see Supplementary Material).…”

Section: Resultsmentioning

confidence: 99%

Interactions of the Melanocortin-4 Receptor with the Peptide Agonist NDP-MSH

Chapman

Kinsella

Cox

et al. 2010

Journal of Molecular Biology

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Melanocortin-4 receptor (MC4R) has an important regulatory role in energy homeostasis and food intake. Peptide agonists of the MC4R are characterized by the conserved sequence His6-Phe7-Arg8-Trp9, which is crucial for their interaction with the receptor. This investigation utilized the covalent attachment approach to identify receptor residues in close proximity to the bound ligand [Nle4,d-Phe7]melanocyte-stimulating hormone (NDP-MSH), thereby differentiating between residues directly involved in ligand binding and those mutations that compromise ligand binding by inducing conformational changes in the receptor. Also, recent X-ray structures of G-protein-coupled receptors were utilized to refine a model of human MC4R in the active state (R⁎), which was used to generate a better understanding of the binding mode of the ligand NDP-MSH at the atomic level.The mutation of residues in the human MC4R—such as Leu106 of extracellular loop 1, and Asp122, Ile125, and Asp126 of transmembrane (TM) helix 3, His264 (TM6), and Met292 (TM7)—to Cys residues produced definitive indications of proximity to the side chains of residues in the core region of the peptide ligand. Of particular interest was the contact between d-Phe7 on the ligand and Ile125 of TM3 on the MC4R. Additionally, Met292 (TM7) equivalent to Lys(7.45) (Ballesteros numbering scheme) involved in covalently attaching retinal in rhodopsin is shown to be in close proximity to Trp9.For the first time, the interactions between the terminal regions of NDP-MSH and the receptor are described. The amino-terminus appears to be adjacent to a series of hydrophilic residues with novel interactions at Cys196 (TM5) and Asp189 (extracellular loop 2). These interactions are reminiscent of sequential ligand binding exhibited by the β2-adrenergic receptor, with the former interaction being equivalent to the known interaction involving Ser204 of the β2-adrenergic receptor.

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“…MC4R has been reported to display constitutive activity, since it increases basal cAMP production in the absence of ligand (50) by spontaneously mimicking an agonist-occupied state (59). Several in vitro experiments have demonstrated that AGRP binding to MC4R decreases basal cAMP production (18,20,33,36,50,59) to suppress constitutive activity of the receptor. This suggests that AGRP not only blocks the agonist activity but also stabilizes the inactive conformation of the receptor and thus either suppresses or reduces the constitutive activity as an inverse agonist does.…”

mentioning

confidence: 99%

Phosphodiesterase inhibitor-dependent inverse agonism of agouti-related protein on melanocortin 4 receptor in sea bass (Dicentrarchus labrax)

Sánchez¹,

Rubio²,

Thompson³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor mainly expressed in the central nervous system of vertebrates. Activation of the MC4R leads to a decrease in food intake, whereas inactivating mutations are a genetic cause of obesity. The binding of agouti-related protein (AGRP) reduces not only agonist-stimulated cAMP production (competitive antagonist) but also the basal activity of the receptor, as an inverse agonist. Transgenic zebrafish overexpressing AGRP display increased food intake and linear growth, indicative of a physiological role for the melanocortin system in the control of the energy balance in fish. We report on the cloning, pharmacological characterization, tissue distribution, and detailed brain mapping of a sea bass (Dicentrarchus labrax) MC4R ortholog. Sea bass MC4R is profusely expressed within food intake-controlling pathways of the fish brain. However, the activity of the melanocortin system during progressive fasting does not depend on the hypothalamic/pituitary proopiomelanocortin (POMC) and MC4R expression, which suggests that sea bass MC4R is constitutively activated and regulated by AGRP binding. We demonstrate that AGRP acts as competitive antagonist and reduces MTII-induced cAMP production. AGRP also decreases the basal activity of the receptor as an inverse agonist. This observation suggests that MC4R is constitutively active and supports the evolutionary conservation of the AGRP/MC4R interactions. The inverse agonism, but not the competitive antagonism, depends on the presence of a phosphodiesterase inhibitor (IBMX). This suggests that inverse agonism and competitive antagonism operate through different intracellular signaling pathways, a view that opens up new targets for the treatment of melanocortin-induced metabolic syndrome.

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Role of third intracellular loop of the melanocortin 4 receptor in the regulation of constitutive activity

Cited by 19 publications

References 21 publications

Greater Impact of Melanocortin-4 Receptor Deficiency on Rates of Growth and Risk of Type 2 Diabetes During Childhood Compared With Adulthood in Pima Indians

Greater Impact of Melanocortin-4 Receptor Deficiency on Rates of Growth and Risk of Type 2 Diabetes During Childhood Compared With Adulthood in Pima Indians

Interactions of the Melanocortin-4 Receptor with the Peptide Agonist NDP-MSH

Phosphodiesterase inhibitor-dependent inverse agonism of agouti-related protein on melanocortin 4 receptor in sea bass (Dicentrarchus labrax)

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