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Annual Meeting of the North American Society for Pediatric Gastroenterology and Nutrition; Orlando, October 22-24, 1998


Yang, Y-K.; Thompson, D.; Wilken, J.; Barsh, G.; Kent, S.B.H.; Gantz, I.; Dickinson, C.

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Journal of Pediatric Gastroenterology & Nutrition: October 1998 - Volume 27 - Issue 4 - p 475
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Abstract 50

We have previously identified 5 subtypes of human melanocortin receptors (MCR). Agouti protein is an antagonist of melanocortin action at MCR1 and is responsible for coat color changes seen in agouti mice. To determine if its relative, AGRP, is also a naturally occurring antagonist of melanocortins we compared the abilities of two highly homogenous synthetic AGRP proteins to inhibit α-MSH binding and α-MSH-induced cAMP accumulation. Human MCR subtypes 1-5 were expressed in HEK 293 cells. Mouse [Leu127Pro]AGRP (mature AGRP minus its signal sequence) inhibited α-MSH-stimulated cAMP activity and 125I-NDP-α-MSH binding in cells expressing MCR3 and MCR4 but not MCR 1 or 2. Significantly, a truncated protein consisting of the C-terminal cysteine-rich domain of human AGRP (residues 87-132) that we refer to as MARP (Minimized Agouti-Related Protein) possessed the same protein activities as mouse [Leu127Pro]AGRP. AGRP and MARP had similar effects on MCR5 but with less potency (IC50 20× greater). Schild analysis indicates that both synthetic AGRP molecules act as competitive antagonists at MCR3, MCR4, and MCR5. In both conventional and photoemulsion binding studies, the radioligand 125I-MARP was observed only to bind to cells expressing melanocortin receptors MC3R, MC4R, and MC5R. Since mice with targeted disruption of MCR4 are obese with altered satiety signals it suggests a possible role for this naturally occurring selective MCR antagonist (AGRP) in obesity. These data have important implications for structural studies of AGRP, anti-obesity drug development and obesity research.

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Transport/Cell Biology/Nutrition

© 1998 Lippincott Williams & Wilkins, Inc.