Molecular pharmacology of neural melanocortin receptors.
The cloning of melanocortin receptors opened new avenues to identify selective ligands for this receptor family. gamma-MSH was characterized as a melanocortin-3 receptor selective agonist, [D-Arg8]ACTH-(4-10) and [Pro8,10, Gly9]ACTH-(4-10) were characterized as melanocortin-4 receptor antagonists. The application of these ligands in vivo revealed that melanocortin-4 receptors mediate melanocortin-induced grooming behaviour in the rat. Since we still lack potent and selective melanocortin receptor ligands, we performed homology modelling and site directed mutagenesis of the melanocortin-4 receptor, in order to understand how melanocortins bind melanocortin receptors. A histidine at position 260 in the melanocortin-4 receptor is important for normal receptor function. However this residue is not forming a salt bridge with a glutamate at position 92 to keep the receptor in an inactive conformation, nor with the glutamate in the melanocortin peptides as had been suggested before.
Adan
R A
RA
Department of Medical Pharmacology, Rudolf Magnus Institute for Neurosciences, Utrecht University, The Netherlands.
Oosterom
J
J
Toonen
R F
RF
Kraan
M V
MV
Burbach
J P
JP
Gispen
W H
WH
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D051381:Rats; D017208:Rats, Wistar; D018043:Receptors, Corticotropin / Q000235:genetics / Q000378:metabolism*; D044101:Receptors, Melanocortin; D000521:alpha-MSH / Q000378:metabolism
D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; D000521:alpha-MSH