Functional role, structure, and evolution of the melanocortin-4 receptor.
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.
Schiöth
Helgi B
HB
Department of Neuroscience, Uppsala University, BMC, 751 24, Uppsala, Sweden. helgis@bmc.uu.se
Lagerström
Malin C
MC
Watanobe
Hajime
H
Jonsson
Logi
L
Vergoni
Anna Valeria
AV
Ringholm
Aneta
A
Skarphedinsson
Jon O
JO
Skuladottir
Gudrun V
GV
Klovins
Janis
J
Fredriksson
Robert
R
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
D008670:Metals; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D000521:alpha-MSH