PUBLICATION

Functional role, structure, and evolution of the melanocortin-4 receptor

Authors
Schiöth, H.B., Lagerström, M.C., Watanobe, H., Jonsson, L., Vergoni, A.V., Ringholm, A., Skarphedinsson, J.O., Skuladottir, G.V., Klovins, J., and Fredriksson, R.
ID
ZDB-PUB-030716-3
Date
2003
Source
Annals of the New York Academy of Sciences   994: 74-83 (Journal)
Registered Authors
Fredriksson, Robert, Ringholm, Aneta
Keywords
none
MeSH Terms
  • Animals
  • Eating*
  • Humans
  • Hypothalamus/metabolism
  • Metals/metabolism
  • Phylogeny
  • Receptor, Melanocortin, Type 4
  • Receptors, Corticotropin/chemistry
  • Receptors, Corticotropin/classification
  • Receptors, Corticotropin/genetics
  • Receptors, Corticotropin/metabolism*
  • Reproduction/physiology
  • alpha-MSH/agonists
  • alpha-MSH/metabolism
PubMed
12851300 Full text @ Ann N Y Acad Sci
Abstract
The melanocortin (MC)-4 receptor participates in regulating body weight homeostasis. We demonstrated early that acute blockage of the MC-4 receptor increases food intake and relieves anorexic conditions in rats Our recent studies show that 4-week chronic blockage of the MC-4 receptor leads to robust increases in food intake and development of obesity, whereas stimulation of the receptor leads to anorexia. Interestingly, the food conversion ratio was clearly increased by MC-4 receptor blockage, whereas it was decreased in agonist-treated rats in a transient manner. Chronic infusion of an agonist caused a transient increase in oxygen consumption. Our studies also show that the MC-4 receptor plays a role in luteinizing hormone and prolactin surges in female rats. The MC-4 receptor has a role in mediating the effects of leptin on these surges. The phylogenetic relation of the MC-4 receptor to other GPCRs in the human genome was determined. The three-dimensional structure of the protein was studied by construction of a high-affinity zinc binding site between the helices, using two histidine residues facing each other. We also cloned the MC-4 receptor from evolutionary important species and showed by chromosomal mapping a conserved synteny between humans and zebrafish. The MC-4 receptor has been remarkably conserved in structure and pharmacology for more than 400 million years , implying that the receptor participated in vital physiological functions early in vertebrate evolution.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping