title: The Melanocortin Receptor Accessory Protein 2 promotes food intake through inhibition of the Prokineticin Receptor-1.
abstract: 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.
authors.affiliation: Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, United States.|Fraternal Order of Eagle Diabetes Research Center, University of Iowa, Iowa City, United States.|Pappajohn Biomedical Institute, University of Iowa, Iowa City, United States.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Chaly
authors.affiliation: Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, United States.|Fraternal Order of Eagle Diabetes Research Center, University of Iowa, Iowa City, United States.|Pappajohn Biomedical Institute, University of Iowa, Iowa City, United States.
authors.forename: Dollada
authors.initials: D
authors.lastname: Srisai
authors.affiliation: Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, United States.|Fraternal Order of Eagle Diabetes Research Center, University of Iowa, Iowa City, United States.|Pappajohn Biomedical Institute, University of Iowa, Iowa City, United States.
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Gardner
authors.affiliation: Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, United States.|Fraternal Order of Eagle Diabetes Research Center, University of Iowa, Iowa City, United States.|Pappajohn Biomedical Institute, University of Iowa, Iowa City, United States.
authors.forename: Julien A
authors.identifier: http://orcid.org/0000-0002-8366-312X
authors.initials: JA
authors.lastname: Sebag
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D004435:Eating; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000737:chemistry; D058261:Receptor Activity-Modifying Proteins / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C582669:MRAP2 protein, mouse; C525015:PKR1 protein, mouse; D058261:Receptor Activity-Modifying Proteins; D043562:Receptors, G-Protein-Coupled
keywords: MRAP2; PKR1; accessory protein; cell biology; melanocortin; mouse; neuroscience; obesity; prokineticin
references.citation: Biochem Biophys Res Commun. 2002 May 17;293(4):1161-7
references.pmid: 12054497
references.citation: Mol Pharmacol. 2001 Apr;59(4):692-8
references.pmid: 11259612
references.citation: Ann N Y Acad Sci. 2003 Jun;994:240-5
references.pmid: 12851322
references.citation: Eur J Pharmacol. 1999 Mar 12;369(1):11-5
references.pmid: 10204675
references.citation: Cell. 2004 Nov 24;119(5):679-91
references.pmid: 15550249
references.citation: Nat Genet. 2005 Feb;37(2):166-70
references.pmid: 15654338
references.citation: Ann N Y Acad Sci. 2006 Jul;1070:90-104
references.pmid: 16888151
references.citation: Trends Biochem Sci. 2006 Nov;31(11):631-8
references.pmid: 17010614
references.citation: FASEB J. 2007 Sep;21(11):2980-93
references.pmid: 17442730
references.citation: Placenta. 2007 Oct;28(10):1049-58
references.pmid: 17531315
references.citation: Endocrinology. 2007 Nov;148(11):5531-40
references.pmid: 17673512
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20244-9
references.pmid: 18077336
references.citation: Int J Biochem Cell Biol. 2008;40(9):1679-84
references.pmid: 18440852
references.citation: Endocrinology. 2008 Jul;149(7):3470-7
references.pmid: 18372330
references.citation: J Biol Chem. 2009 Jan 2;284(1):610-8
references.pmid: 18981183
references.citation: Mol Cell Endocrinol. 2009 Mar 5;300(1-2):17-24
references.pmid: 19000738
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 14;106(15):6146-51
references.pmid: 19329486
references.citation: J Biol Chem. 2009 Aug 21;284(34):22641-8
references.pmid: 19535343
references.citation: Ann N Y Acad Sci. 2009 Jul;1170:153-6
references.pmid: 19686127
references.citation: Nat Rev Mol Cell Biol. 2009 Dec;10(12):819-30
references.pmid: 19935667
references.citation: Diabetes. 2010 Feb;59(2):397-406
references.pmid: 19933997
references.citation: Cardiovasc Res. 2011 Nov 1;92(2):191-8
references.pmid: 21856786
references.citation: Curr Pharm Biotechnol. 2011 Oct;12(10):1720-7
references.pmid: 21466441
references.citation: Regul Pept. 2012 Nov 10;179(1-3):84-90
references.pmid: 22960406
references.citation: Br J Pharmacol. 2013 Jan;168(2):403-10
references.pmid: 22935107
references.citation: Gen Comp Endocrinol. 2013 Jul 1;188:133-6
references.pmid: 23410915
references.citation: Science. 2013 Jul 19;341(6143):275-8
references.pmid: 23869016
references.citation: Science. 2013 Jul 19;341(6143):278-81
references.pmid: 23869017
references.citation: J Am Heart Assoc. 2013 Oct;2(5):e000411
references.pmid: 24152983
references.citation: PLoS One. 2013;8(12):e81175
references.pmid: 24324673
references.citation: J Pharmacol Exp Ther. 2015 May;353(2):246-60
references.pmid: 25650376
references.citation: Neuropeptides. 2002 Apr-Jun;36(2-3):77-84
references.pmid: 12359499