Decreased melanocortin-4 receptor function conferred by an infrequent variant at the human melanocortin receptor accessory protein 2 gene

Obesity ◽  
2016 ◽  
Vol 24 (9) ◽  
pp. 1976-1982 ◽  
Author(s):  
Laura Schonnop ◽  
Gunnar Kleinau ◽  
Nikolas Herrfurth ◽  
Anna-Lena Volckmar ◽  
Cigdem Cetindag ◽  
...  
Keyword(s):  
Melanocortin Receptor ◽  
Accessory Protein ◽  
Receptor Function ◽  
Melanocortin 4 Receptor ◽  
Receptor Accessory Protein

scholarly journals Melanocortin Receptor Accessory Protein 2-Induced Adrenocorticotropic Hormone Response of Human Melanocortin 4 Receptor

2018 ◽  
Vol 3 (2) ◽  
pp. 314-323 ◽  
Author(s):  
Lucia Soletto ◽  
Sergio Hernández-Balfagó ◽  
Ana Rocha ◽  
Patrick Scheerer ◽  
Gunnar Kleinau ◽  
...  
Keyword(s):  
Adrenocorticotropic Hormone ◽  
Melanocortin Receptor ◽  
Accessory Protein ◽  
Hormone Response ◽  
Melanocortin 4 Receptor ◽  
Receptor Accessory Protein

scholarly journals The Melanocortin Receptor Accessory Protein 2 promotes food intake through inhibition of the Prokineticin Receptor-1

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Anna L Chaly ◽  
Dollada Srisai ◽  
Ellen E Gardner ◽  
Julien A Sebag
Keyword(s):  
Food Intake ◽  
Energy Homeostasis ◽  
Severe Obesity ◽  
Melanocortin Receptor ◽  
Accessory Protein ◽  
Important Regulator ◽  
Receptor Accessory Protein

The Melanocortin Receptor Accessory Protein 2 (MRAP2) is an important regulator of energy homeostasis and its loss causes severe obesity in rodents. MRAP2 mediates its action in part through the potentiation of the MC4R, however, it is clear that MRAP2 is expressed in tissues that do not express MC4R, and that the deletion of MRAP2 does not recapitulate the phenotype of Mc4r KO mice. Consequently, we hypothesized that other GPCRs involved in the control of energy homeostasis are likely to be regulated by MRAP2. In this study we identified PKR1 as the first non-melanocortin GPCR to be regulated by MRAP2. We show that MRAP2 significantly and specifically inhibits PKR1 signaling. We also demonstrate that PKR1 and MRAP2 co-localize in neurons and that Mrap2 KO mice are hypersensitive to PKR1 stimulation. This study not only identifies new partners of MRAP2 but also a new pathway through which MRAP2 regulates energy homeostasis.

scholarly journals Melanocortin 4 Receptor Becomes an ACTH Receptor by Coexpression of Melanocortin Receptor Accessory Protein 2

2013 ◽  
Vol 27 (11) ◽  
pp. 1934-1945 ◽  
Author(s):  
Maria Josep Agulleiro ◽  
Raúl Cortés ◽  
Begoña Fernández-Durán ◽  
Sandra Navarro ◽  
Raúl Guillot ◽  
...  
Keyword(s):  
Energy Balance ◽  
Functional Expression ◽  
Melanocortin Receptor ◽  
Positive Energy ◽  
Accessory Protein ◽  
Regulatory Pathways ◽  
Melanocortin 4 Receptor ◽  
Acth Receptor ◽  
Positive Energy Balance ◽  
Melanocortin Signaling

Melanocortin 2 receptor (MC2R) is the only canonical ACTH receptor. Its functional expression requires the presence of an accessory protein, known as melanocortin receptor 2 accessory protein 1 (MRAP1). The vertebrate genome exhibits a paralogue gene called MRAP2, which is duplicated in zebrafish (MRAP2a and MRAP2b), although its function remains unknown. In this paper, we demonstrate that MRAP2a enables MC4R, a canonical MSH receptor, to be activated by ACTH with a similar sensitivity to that exhibited by MC2R. Both proteins physically interact and are coexpressed in the neurons of the preoptic area, a key region in the control of the energy balance and hypophyseal secretion in fish. ACTH injections inhibit food intake in wild-type zebrafish but not in fish lacking functional MC4R. Both MRAP1 and MRAP2a are hormonally regulated, suggesting that these proteins are substrates for feed-back regulatory pathways of melanocortin signaling. Fasting has no effect on the central expression of MRAP2a but stimulates MRAP2b expression. This protein interacts and is colocalized with MC4R in the tuberal hypothalamic neurons but has no effect on the pharmacologic profile of MC4R. However, MRPA2b is able to decrease basal reporter activity in cell lines expressing MC4R. It is plausible that MRAP2b decreases the constitutive activity of the MC4R during fasting periods, driving the animal toward a positive energy balance. Our data indicate that MRAP2s control the activity of MC4R, opening up new pathways for the regulation of melanocortin signaling and, by extension, for the regulation of the energy balance and obesity.

scholarly journals Attractin' more attention – new pieces in the obesity puzzle?

2003 ◽  
Vol 376 (1) ◽  
pp. e7-e8 ◽  
Author(s):  
Giles S. H. YEO ◽  
Kenneth SIDDLE
Keyword(s):  
Transmembrane Protein ◽  
Critical Role ◽  
Family Influence ◽  
Melanocortin Receptor ◽  
Receptor Function ◽  
Melanocortin 4 Receptor ◽  
Biochemical Journal ◽  
Pharmacological Studies ◽  
G Protein Coupled

Genetic, biochemical and pharmacological studies in humans and rodents have established that signalling through the G-protein-coupled melanocortin-4 receptor (MC4R) by pro-opiomelanocortin (POMC)-derived ligands plays a critical role in the central suppression of appetite. As a consequence, malfunction of this signalling system leads to the development of obesity. It has been shown previously that melanocortin signalling can be modulated by the type 1 transmembrane protein attractin, apparently acting as a co-receptor for the inhibitory ligand agouti. Work reported in this issue of Biochemical Journal (Haqq et al.) demonstrates that the cytosolic tail of an attractin-like protein (ALP) binds directly and specifically to the C-terminal region of MC4R, raising the possibility that proteins of the attractin family influence melanocortin receptor function through multiple mechanisms.

Melanocortin 2 receptor accessory protein 2 (Mrap2) regulates hypothalamic melanocortin-4-receptor trafficking in vivo

2014 ◽  
Author(s):  
Tatiana Novoselova ◽  
Rachel Larder ◽  
Debra Rimmington ◽  
Chris Lelliott ◽  
Elizabeth Wynn ◽  
...  
Keyword(s):  
Receptor Trafficking ◽  
Accessory Protein ◽  
Melanocortin 4 Receptor ◽  
Receptor Accessory Protein

scholarly journals Membrane Orientation and Oligomerization of the Melanocortin Receptor Accessory Protein 2

2020 ◽  
Author(s):  
Valerie Chen ◽  
Antonio E. Bruno ◽  
Laura L. Britt ◽  
Ciria C. Hernandez ◽  
Luis E. Gimenez ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Membrane Topology ◽  
Melanocortin Receptor ◽  
Accessory Protein ◽  
Metabolic Dysfunction ◽  
Loss Of Function ◽  
Membrane Orientation ◽  
Eukaryotic Proteins ◽  
G Protein Coupled ◽  
Receptor Accessory Protein

ABSTRACTThe melanocortin receptor accessory protein 2 (MRAP2) plays a pivotal role in the regulation of several G-protein coupled receptors (GPCR) that are essential for energy balance and food intake. MRAP2 loss-of-function results in obesity in mammals. MRAP2 and its homolog MRAP1 have an unusual membrane topology and are the only known eukaryotic proteins that thread into the membrane in both orientations. In this study, we demonstrate that the conserved polybasic motif that dictates the membrane topology and dimerization of MRAP1 does not control the membrane orientation and dimerization of MRAP2. We also show that MRAP2 dimerizes through its transmembrane domain and can form higher order oligomers that arrange MRAP2 monomers in a parallel orientation. Investigating the molecular details of MRAP2 structure is essential for understanding the mechanism by which it regulates GPCRs and will aid in elucidating the pathways involved in metabolic dysfunction.

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