title: Inverse agonist activity of agouti and agouti-related protein.
abstract: Agouti and agouti-related protein (AgRP) are endogenous antagonists of the melanocortin receptors (MCxR). Previous data showed that recombinant full-length agouti and a synthetic fragment of AgRP, AgRP (83-132), are inverse agonists at the MC1R and MC4R, respectively. This study demonstrates the smaller analogs AgRP (87-120) and ASIP [90-132 (L89Y)], and short peptides Yc[CRFFNAFC]Y and Qc[CRFFRSAC]S are also MC4R inverse agonists. Furthermore, the relative affinity of the series of MC4R ligands for displacement of radiolabeled antagonist 125I-AgRP (86-132) versus radiolabeled agonist 125I-NDP-MSH did not correlate with ligand efficacy, which is more consistent with an induced-fit model than a simple two-state model of MC4R activation. These data shed new light on the determinants and mechanism of inverse agonism at the MC4R.
authors.affiliation: Department of Surgery, University of Michigan Medical Center, Ann Arbor 48109-0682, USA.
authors.forename: Biao-Xin
authors.initials: BX
authors.lastname: Chai
authors.forename: Richard R
authors.initials: RR
authors.lastname: Neubig
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Millhauser
authors.forename: Darren A
authors.initials: DA
authors.lastname: Thompson
authors.forename: Pilgrim J
authors.initials: PJ
authors.lastname: Jackson
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Barsh
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Dickinson
authors.forename: Ji-Yao
authors.initials: JY
authors.lastname: Li
authors.forename: Yu-Mei
authors.initials: YM
authors.lastname: Lai
authors.forename: Ira
authors.initials: I
authors.lastname: Gantz
mesh_terms: D054366:Agouti Signaling Protein; D054369:Agouti-Related Protein; D020816:Amino Acid Motifs; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007031:Hypothalamus / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D007700:Kinetics; D008024:Ligands; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D008958:Models, Molecular; D009765:Obesity; D010455:Peptides / Q000737:chemistry; D010456:Peptides, Cyclic / Q000494:pharmacology; D010858:Pigmentation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000502:physiology*; D044101:Receptors, Melanocortin / Q000037:antagonists & inhibitors / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D000521:alpha-MSH / Q000378:metabolism; D019824:beta-MSH / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C471568:11-Mrp-14-Nal-18-Cys-22-Asp-beta-MSH(11-22)NH2; C515198:AGRP protein, human; D054366:Agouti Signaling Protein; D054369:Agouti-Related Protein; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D010455:Peptides; D010456:Peptides, Cyclic; D011506:Proteins; D044101:Receptors, Melanocortin; D011994:Recombinant Proteins; D019824:beta-MSH; C103272:SHU 9119; D000521:alpha-MSH; D009074:Melanocyte-Stimulating Hormones; D000242:Cyclic AMP