Agouti-related protein functions as an inverse agonist at a constitutively active brain melanocortin-4 receptor

Agouti-related protein functions as an inverse agonist at a constitutively active brain... Agouti-related protein (AGRP) is one of two naturally occurring antagonists of G-Protein coupled receptors (GPCRs) identified to date, and has been physiologically implicated in regulating food intake, body weight, and energy homeostasis. AGRP has been identified in vitro, as competitively antagonizing the brain melanocortin-4 (MC4R) and melanocortin-3 (MC3R) receptors, and when over expressed in transgenic mice, results in an obese phenotype. Emerging data propose that AGRP has additional targets in the hypothalamus and/or physiologically functions via a mechanism in addition to competitive antagonism of α-MSH at the brain melanocortin receptors. We report data herein supporting an alternative mechanism for AGRP involvement in feeding behavior. A constitutively active MC4R has been generated which possess EC 50 values for melanocortin agonists (α-MSH, NDP-MSH, and MTII) and a p A 2 value for the synthetic peptide antagonist SHU9119 identical to the wildtype receptor, but increases basal activity to 50% maximal response. AGRP possesses inverse agonist activity at this constitutively active MC4R. These data support the hypothesis for an additional physiological mechanism for AGRP action in feeding behavior and energy homeostasis. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Regulatory Peptides Elsevier

Agouti-related protein functions as an inverse agonist at a constitutively active brain melanocortin-4 receptor

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Publisher
Elsevier
Copyright
Copyright © 2001 Elsevier Science B.V.
ISSN
0167-0115
eISSN
1873-1686
DOI
10.1016/S0167-0115(01)00234-8
Publisher site
See Article on Publisher Site

Abstract

Agouti-related protein (AGRP) is one of two naturally occurring antagonists of G-Protein coupled receptors (GPCRs) identified to date, and has been physiologically implicated in regulating food intake, body weight, and energy homeostasis. AGRP has been identified in vitro, as competitively antagonizing the brain melanocortin-4 (MC4R) and melanocortin-3 (MC3R) receptors, and when over expressed in transgenic mice, results in an obese phenotype. Emerging data propose that AGRP has additional targets in the hypothalamus and/or physiologically functions via a mechanism in addition to competitive antagonism of α-MSH at the brain melanocortin receptors. We report data herein supporting an alternative mechanism for AGRP involvement in feeding behavior. A constitutively active MC4R has been generated which possess EC 50 values for melanocortin agonists (α-MSH, NDP-MSH, and MTII) and a p A 2 value for the synthetic peptide antagonist SHU9119 identical to the wildtype receptor, but increases basal activity to 50% maximal response. AGRP possesses inverse agonist activity at this constitutively active MC4R. These data support the hypothesis for an additional physiological mechanism for AGRP action in feeding behavior and energy homeostasis.

Journal

Regulatory PeptidesElsevier

Published: May 5, 2001

References

  • Effects of neuropeptide Y deficiency on hypothalamic agouti-related protein expression and responsiveness to melanocortin analogues
    Marsh, D.J; Miura, G.I; Yagaloff, K.A; Schwartz, M.W; Barsh, G.S; Palmiter, R.D
  • Long-term orexigenic effects of AgRP-(83–132) involve mechanisms other than melanocortin receptor blockade
    Hagan, M.M; Rushing, P.A; Pritchard, L.M; Schwartz, M.W; Strack, A.M; Van Der Ploeg, L.H
  • Structure activity studies of the melanocortin antagonist SHU9119 modified at the 6, 7, 8, and 9 positions
    Haskell-Luevano, C; Lim, S; Yuan, W; Cone, R.D; Hruby, V.J

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