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Title: Agouti-related protein is posttranslationally cleaved by proprotein convertase 1 to generate agouti-related protein (AGRP)(83-132): Interaction between AGRP(83-132) and melanocortin receptors cannot be influenced by syndecan-3
Authors: Creemers, John
Pritchard, Le
Gyte, A
Le Rouzic, P
Meulemans, S
Wardlaw, Sl
Zhu, Xr
Steiner, Df
Davies, N
Armstrong, D
Lawrence, Cb
Luckman, Sm
Schmitz, Ca
Davies, Ra
Brennand, Jc
White, A #
Issue Date: 2006
Series Title: Endocrinology vol:147 issue:4 pages:1621-1631
Abstract: Agouti- related protein ( AGRP) plays a key role in energy homeostasis. The carboxyl-terminal domain of AGRP acts as an endogenous antagonist of the melanocortin-4 receptor (MC4-R). It has been suggested that the amino-terminal domain of AGRP binds to syndecan-3, thereby modulating the effects of carboxyl-terminal AGRP at the MC4-R. This model assumes thatAGRPis secreted as a full-length peptide. In this study we found that AGRP is processed intracellularly after Arg79Glu80- Pro81-Arg82. The processing site suggests cleavage by proprotein convertases (PCs). RNA interference and overexpression experiments showed that PC1/3 is primarily responsible for cleavage in vitro, although both PC2 and PC5/6A can also process AGRP. Dual in situ hybridization demonstrated that PC1/3 is expressed in AGRP neurons in the rat hypothalamus. Moreover, hypothalamic extracts from PC1-null mice contained 3.3- fold more unprocessed full-length AGRP, compared with wild-type mice, based on combined HPLC and RIA analysis, demonstrating that PC1/3 plays a role in AGRP cleavage in vivo. We also found that AGRP83-132 is more potent an antagonist than full-length AGRP, based on cAMP reporter assays, suggesting that posttranslational cleavage is required to potentiate the effect of AGRP at the MC4-R. Because AGRP is cleaved into distinct amino-terminal and carboxyl-terminal peptides, we tested whether amino-terminal peptides modulate food intake. However, intracerebroventricular injection of rat AGRP25-47 and AGRP50-80 had no effect on body weight, food intake, or core body temperature. Because AGRP is cleaved before secretion, syndecan-3 must influence food intake independently of the MC4-R.
ISSN: 0013-7227
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Genetics Section (-)
Department of Human Genetics - miscellaneous
# (joint) last author

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