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Developmental control of the melanocortin-4 receptor by MRAP2 proteins in zebrafish.

The melanocortin-4 receptor (MC4R) is essential for control of energy homeostasis in vertebrates. MC4R interacts with melanocortin receptor accessory protein 2 (MRAP2) in vitro, but its functions in vivo are unknown. We found that MRAP2a, a larval form, stimulates growth of zebrafish by specifically blocking the action of MC4R. In cell culture, this protein binds MC4R and reduces the ability of the receptor to bind its ligand, α-melanocyte-stimulating hormone (α-MSH). A paralog, MRAP2b, expressed later in development, also binds MC4R but increases ligand sensitivity. Thus, MRAP2 proteins allow for developmental control of MC4R activity, with MRAP2a blocking its function and stimulating growth during larval development, whereas MRAP2b enhances responsiveness to α-MSH once the zebrafish begins feeding, thus increasing the capacity for regulated feeding and growth.

Pubmed ID: 23869017


  • Sebag JA
  • Zhang C
  • Hinkle PM
  • Bradshaw AM
  • Cone RD


Science (New York, N.Y.)

Publication Data

July 19, 2013

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK020593
  • Agency: NIDDK NIH HHS, Id: DK070332
  • Agency: NIDDK NIH HHS, Id: DK075721
  • Agency: NIDDK NIH HHS, Id: DK19974
  • Agency: NIDDK NIH HHS, Id: F23DK091055
  • Agency: NIDDK NIH HHS, Id: R01 DK070332
  • Agency: NIDDK NIH HHS, Id: R01 DK075721
  • Agency: NIDDK NIH HHS, Id: T32 DK007563

Mesh Terms

  • Animals
  • Embryo, Nonmammalian
  • Energy Metabolism
  • HEK293 Cells
  • Humans
  • Receptor Activity-Modifying Proteins
  • Receptor, Melanocortin, Type 4
  • Zebrafish
  • Zebrafish Proteins
  • alpha-MSH