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

Carrie Haskell-Luevano; Eileen K. Monck

doi:10.1016/S0167-0115(01)00234-8

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

Carrie Haskell-Luevano
, Eileen K. Monck

Research output: Contribution to journal › Article › peer-review

230 Scopus citations

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 EC₅₀ values for melanocortin agonists (α-MSH, NDP-MSH, and MTII) and a pA₂ 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.

Original language	English (US)
Pages (from-to)	1-7
Number of pages	7
Journal	Regulatory Peptides
Volume	99
Issue number	1
DOIs	https://doi.org/10.1016/S0167-0115(01)00234-8
State	Published - May 5 2001
Externally published	Yes

Bibliographical note

Funding Information:
This work has been funded by NIH Grant RO1-DK57080-01 (C.H.L.), the Howard Hughes Medical Institute Research Resources Program, University of Florida and Carrie Haskell-Luevano is a recipient of a Burroughs Wellcome fund Career Award in the Biomedical Sciences.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Energy Homeostasis
Feeding
MC4R
Melanotropin
Neuropeptide
Obesity

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10.1016/S0167-0115(01)00234-8

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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 EC50 values for melanocortin agonists (α-MSH, NDP-MSH, and MTII) and a pA2 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.",

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note = "Funding Information: This work has been funded by NIH Grant RO1-DK57080-01 (C.H.L.), the Howard Hughes Medical Institute Research Resources Program, University of Florida and Carrie Haskell-Luevano is a recipient of a Burroughs Wellcome fund Career Award in the Biomedical Sciences.",

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

Abstract

Bibliographical note

UN SDGs

Keywords

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