title: Comparative pharmacological studies of melatonin receptors: MT1, MT2 and MT3/QR2. Tissue distribution of MT3/QR2 .
abstract: The neurohormone melatonin is the central switch of the circadian rhythm and presumably exerts its activities through a series of receptors among which MT1 and MT2 have been widely studied. The third binding site of melatonin, MT3, has been recently characterized as a melatonin-sensitive form of the quinone reductase 2 (QR2, EC 1.6.99.2). In the present work, we showed that the binding of melatonin at MT3/QR2 was better described with 2-[125I]-iodomethoxy-carbonylamino-N-acetyltryptamine (2-[125I]-I-MCA-NAT) and, most importantly, that it was measurable at 20 degrees while it has been initially described and thoroughly studied using 2-[125I]-iodomelatonin at 4 degrees. Under these novel conditions, binding to MT3 could be traced without cross-reactivity with MT1 and MT2 receptors and, moreover, under conditions similar to those used to measure MT3/QR2 catalytic activity. The pharmacology established here on hamster kidney samples using the reference compounds remained essentially as already described using other experimental conditions. A new series of compounds with nanomolar affinity for the MT3 binding site and a high MT3 selectivity versus MT1 and MT2 is reported. In addition, we further document the MT3/QR2 binding site by demonstrating that it was widely distributed among mammals, although inter-species and inter-tissues differences exist. The present report details new experimental conditions for the pharmacological study of melatonin-sensitive QR2 isoforms, and suggests that, in addition to an already demonstrated inter-species difference, inter-tissues differences in QR2 sensitivity to melatonin may exist in primates and, therefore, represent an original and interesting route of investigation on the effect of melatonin on MT3/QR2.
authors.affiliation: Pharmacologie Moléculaire et Cellulaire, Institut de Recherches Servier, 78290-Croissy-sur-Seine, France.
authors.forename: O
authors.initials: O
authors.lastname: Nosjean
authors.forename: J P
authors.initials: JP
authors.lastname: Nicolas
authors.forename: F
authors.initials: F
authors.lastname: Klupsch
authors.forename: P
authors.initials: P
authors.lastname: Delagrange
authors.forename: E
authors.initials: E
authors.lastname: Canet
authors.forename: J A
authors.initials: JA
authors.lastname: Boutin
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002478:Cells, Cultured; D006224:Cricetinae; D006801:Humans; D007457:Iodine Radioisotopes; D007700:Kinetics; D008550:Melatonin / Q000031:analogs & derivatives / Q000494:pharmacology; D000090023:Metallothionein 3; D051379:Mice; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044094:Receptors, Melatonin; D013045:Species Specificity; D013696:Temperature; D014018:Tissue Distribution; D014363:Tryptamines / Q000494:pharmacology
chemical_list: D007457:Iodine Radioisotopes; D000090023:Metallothionein 3; C000715430:Mt3 protein, mouse; C408803:N-pentanoyl-2-benzyltryptamine; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D014363:Tryptamines; C044556:2-iodomelatonin; D008550:Melatonin