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Differential regulation of cAMP-mediated gene transcription and ligand selectivity by MC3R and MC4R melanocortin receptors

 Eun Jin Lee  ;  Soo-Hyun Lee  ;  Jin-Won Jung  ;  Weontae Lee  ;  Byung Jin Kim  ;  Kye Won Park  ;  Sung-Kil Lim  ;  Chang-Ju Yoon  ;  Ja-Hyun Baik 
 EUROPEAN JOURNAL OF BIOCHEMISTRY , Vol.268(3) : 582-591, 2001 
Journal Title
Issue Date
Adrenocorticotropic Hormone/analogs & derivatives ; Adrenocorticotropic Hormone/chemistry ; Adrenocorticotropic Hormone/metabolism* ; Amino Acids/chemistry ; Animals ; Binding Sites ; Blotting, Northern ; CHO Cells ; Cell Line ; Cricetinae ; Cyclic AMP/metabolism* ; Gene Expression Regulation* ; Genes, Reporter ; Humans ; Ligands ; Luciferases/metabolism ; Magnetic Resonance Spectroscopy ; Models, Chemical ; Models, Molecular ; Mutation ; Protein Binding ; Receptor, Melanocortin, Type 3 ; Receptor, Melanocortin, Type 4 ; Receptors, Corticotropin/chemistry ; Receptors, Corticotropin/metabolism* ; Response Elements ; Time Factors ; Transcription, Genetic* ; alpha-MSH/chemistry ; alpha-MSH/metabolism
cAMP ; G-protein ; melanocortin ; molecular modeling ; obesity
Melanocortins are known to be involved in the regulation of feeding behavior. These hormones mediate their effects through G-protein-coupled receptors by stimulating adenylate cyclase. In this study we describe the functional response of melanocortin 4 receptor (MC4R) and melanocortin 3 receptor (MC3R) in HEK 293T cells, by using a luciferase reporter gene under the transcriptional control of a cAMP-responsive element (CRE) as a monitor of intracellular cAMP levels and cAMP-regulated gene expression. We were able to show that MC4R and MC3R expressed in the human cell line HEK 293T stimulate transcription induced by stimulation with different analogs of α-melanocyte-stimulating hormone (α-MSH) at different levels. In our assay of CRE-mediated gene transcription activity, α-MSH-ND was the most efficient α-MSH analog for MC4R whereas NDP-MSH was the most efficient for MC3R. Changing the His6 residue of α-MSH-ND to Gln or Lys markedly decreased CRE-mediated luciferase activity for MC3R compared with MC4R. On analysis by modeling the receptor–ligand complex by NMR, [Gln6]α-MSH-ND and [Lys6]α-MSH-ND showed different conformational interactions between MC3R and MC4R. Furthermore, the maximum coupling efficiency of MC4R and MC3R to G proteins was different; MC4R showed only 30–50% of the maximum activity induced by MC3R. In total, our results suggest that a differential receptor–ligand interaction is involved and that the relative interactions of MC3R and MC4R with G protein are possibly quantitatively and qualitatively different.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Lim, Sung Kil(임승길)
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