Cell Surface Expression of the Melanocortin-4 Receptor Is Dependent on a C-terminal Di-isoleucine Sequence at Codons 316/317

VanLeeuwen, Donald; Steffey, Michael E.; Donahue, Christopher J.; Ho, Guyu; MacKenzie, Robert G.

doi:10.1074/jbc.m211546200

Cited by 49 publications

(37 citation statements)

References 24 publications

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“…4B, first row, EV). This result is consistent with previous findings that MC4R I316S has tendency to be retained in the ER (8,30,31,35,50). The ratio of red fluorescence (Cy3, recycling receptor) to green fluorescence (GFP, total receptor) is a measure of the fraction of total HA-MC4R-GFP that has exited the biosynthetic pathway to reach the cell surface and recycle (31).…”

Section: Binding Of Intracellular α-Msh To Obesity-linked Mc4r Variansupporting

confidence: 80%

Exposure of MC4R to agonist in the endoplasmic reticulum stabilizes an active conformation of the receptor that does not desensitize

Granell

Molden

Baldini

2013

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

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Melanocortin-4 receptor (MC4R) is a G protein-coupled receptor expressed in neurons of the hypothalamus where it regulates food intake. MC4R responds to an agonist, α-melanocyte-stimulating hormone (α-MSH) and to an antagonist/inverse agonist, agoutirelated peptide (AgRP), which are released by upstream neurons. Binding to α-MSH leads to stimulation of receptor activity and suppression of food intake, whereas AgRP has opposite effects. MC4R cycles constantly between the plasma membrane and endosomes and undergoes agonist-mediated desensitization by being routed to lysosomes. MC4R desensitization and increased AgRP expression are thought to decrease the effectiveness of MC4R agonists as an antiobesity treatment. In this study, α-MSH, instead of being delivered extracellularly, is targeted to the endoplasmic reticulum (ER) of neuronal cells and cultured hypothalamic neurons. We find that the ER-targeted agonist associates with MC4R at this location, is transported to the cell surface, induces constant cAMP and AMP kinase signaling at maximal amplitude, abolishes desensitization of the receptor, and promotes both cell-surface expression and constant signaling by an obesity-linked MC4R variant, I316S, that otherwise is retained in the ER. Formation of the MC4R/agonist complex in the ER stabilizes the receptor in an active conformation that at the cell surface is insensitive to antagonism by AgRP and at the endosomes is refractory to routing to the lysosomes. The data indicate that targeting agonists to the ER can stabilize an active conformation of a G protein-coupled receptor that does not become desensitized, suggesting a target for therapy. M elanocortin-4 receptor (MC4R) is a G protein-coupled receptor (GPCR) expressed in the brain where it controls food intake and energy expenditure (1-3). MC4R-knockout mice are obese (4), as are humans with naturally occurring mutations of the receptor (5-8), thus indicating the central importance of MC4R in energy homeostasis. Although MC4R is expressed ubiquitously in the central nervous system (9, 10), regulation of food intake is restored in MC4R-knockout mice when MC4R is expressed in the paraventricular nuclei of the hypothalamus and in the amygdala (11). Multiple anorexigenic hormones from the periphery, including leptin from the adipose tissue, insulin from β-cells of the pancreas, and glucagon-like peptide-1 and cholecystokinin from the gut, are received by pro-opiomelanocortin (POMC) neurons localized in the arcuate nucleus of the hypothalamus. POMC neurons, projecting to the paraventricular nucleus of the hypothalamus, release the anorexigenic hormone α-melanocyte-stimulating hormone (α-MSH), which binds to MC4R expressed by downstream melanocortin neurons. On the other hand, other neurons in the arcuate nucleus that respond to orexigenic hormones from the periphery increase the production of agouti-related protein (AgRP), which is the natural antagonist/inverse agonist of MC4R (12-18). AgRP signaling and AgRP neurons (19-21) appear to be essential to promote feedin...

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Section: Binding Of Intracellular α-Msh To Obesity-linked Mc4r Variansupporting

confidence: 80%

Exposure of MC4R to agonist in the endoplasmic reticulum stabilizes an active conformation of the receptor that does not desensitize

Granell

Molden

Baldini

2013

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

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“…Highly conserved among species, isoleucine-317 may exert an important functional role. A functional study is required to test whether this variant is associated with reduced MC4R membrane expression and ␣-MSH response as shown for the I317T variant (14,15,31,32,35,36 ).…”

Section: Discussionmentioning

confidence: 99%

Six Novel Mutations in the Proopiomelanocortin and Melanocortin Receptor 4 Genes in Severely Obese Adults Living in Southern Italy

Buono

Pasanisi

Nardelli³

et al. 2005

Clinical Chemistry

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Background:The genetic characterization of obese individuals could clarify the molecular mechanisms underlying body weight regulation and lead to targeted therapy. Here we report variants of the proopiomelanocortin (POMC) and melanocortin receptor 4 (MC4R) genes detected in severely obese adults living in southern Italy. Methods: A total of 196 unrelated nondiabetic severely obese individuals [111 females and 85 males; mean (SD) age, 32.2 (11.5) years; mean body mass index, 48.8 (8.1) kg/m 2 ] and 100 normal-weight healthy volunteers (34 males and 66 females) entered the study. POMC and MC4R were genotyped by sequencing analysis. Leptin, insulin, glucose, and the lipid profile were measured in fasting serum samples. We used the protein truncation test to verify the stop-codon mutation. Anthropometric measurements, sitting blood pressure, and heart rate were also recorded. Results: Of the obese participants, 1.5% had mutations in POMC exon 3 (new mutations, P231L and E244X; known, R236G) and 2.5% had MC4R mutations (new mutations, W174C, Q43X, S19fsX51, and I317V; known, A175T). These mutations were not present in the controls. Gene polymorphisms were identified in similar percentages of severely obese and nonobese individu-

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“…An intriguing aspect of the desensitization process is the myriad of functions attributed to the GPCR C terminus, from harboring putative phosphorylation sites (19), to containing both positive and negative regulators of the endocytotic machinery (19), to serving as an anchor point upon which numerous protein-protein interactions can be built (20,21). Consequently, the functionality of the GPCR C-terminal tail has been greatly expanded in recent years to include a role in receptor trafficking (22)(23)(24), intracellular signaling (25,26), and receptor dimerization (27).…”

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confidence: 99%

Cloning and Characterization of the Pheromone Biosynthesis Activating Neuropeptide Receptor from the Silkmoth, Bombyx mori

Hull

Ohnishi

Moto

et al. 2004

Journal of Biological Chemistry

112

115

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In most Lepidoptera, pheromone biosynthesis is regulated by a neuropeptide termed pheromone biosynthesis activating neuropeptide (PBAN). Although much is known about the cellular targets of PBAN, identification and functional characterization of the PBAN receptor (PBANR) has proven to be elusive. Given the sequence similarity between the active C-terminal regions of PBAN and neuromedin U, it was hypothesized that their respective receptors might also be similar in structure (

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Cell Surface Expression of the Melanocortin-4 Receptor Is Dependent on a C-terminal Di-isoleucine Sequence at Codons 316/317

Abstract: Loss-of-function mutations in the human melanocortin-4 receptor (MC4R) are associated with obesity. Previous work has implicated a C-terminal di-isoleucine motif at residues 316/317 in MC4R cell surface targeting.

Cited by 49 publications

References 24 publications

Exposure of MC4R to agonist in the endoplasmic reticulum stabilizes an active conformation of the receptor that does not desensitize

Exposure of MC4R to agonist in the endoplasmic reticulum stabilizes an active conformation of the receptor that does not desensitize

Six Novel Mutations in the Proopiomelanocortin and Melanocortin Receptor 4 Genes in Severely Obese Adults Living in Southern Italy

Cloning and Characterization of the Pheromone Biosynthesis Activating Neuropeptide Receptor from the Silkmoth, Bombyx mori

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