title: Functional role, structure, and evolution of the melanocortin-4 receptor.
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.
authors.affiliation: Department of Neuroscience, Uppsala University, BMC, 751 24, Uppsala, Sweden. helgis@bmc.uu.se
authors.forename: Helgi B
authors.initials: HB
authors.lastname: Schiöth
authors.forename: Malin C
authors.initials: MC
authors.lastname: Lagerström
authors.forename: Hajime
authors.initials: H
authors.lastname: Watanobe
authors.forename: Logi
authors.initials: L
authors.lastname: Jonsson
authors.forename: Anna Valeria
authors.initials: AV
authors.lastname: Vergoni
authors.forename: Aneta
authors.initials: A
authors.lastname: Ringholm
authors.forename: Jon O
authors.initials: JO
authors.lastname: Skarphedinsson
authors.forename: Gudrun V
authors.initials: GV
authors.lastname: Skuladottir
authors.forename: Janis
authors.initials: J
authors.lastname: Klovins
authors.forename: Robert
authors.initials: R
authors.lastname: Fredriksson
mesh_terms: D000818:Animals; D004435:Eating; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D008670:Metals / Q000378:metabolism; D010802:Phylogeny; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D012098:Reproduction / Q000502:physiology; D000521:alpha-MSH / Q000819:agonists / Q000378:metabolism
chemical_list: D008670:Metals; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D000521:alpha-MSH