Polymorphism and signalling of melatonin receptors

Melatonin receptors belong to the superfamily of G protein-coupled receptors. Cloning of Mellc receptors expressed in Xenopus skin revealed the existence of a polymorphism for these receptors. Heterologous expression of the two allelic isoforms, called Mellc(a) and Mellc([3), indi- cated functional differences in their signalling properties. Both isoforms are coupled to the cAMP and cGMP pathways. However, the a isoform is preferentially coupled to the cAMP pathway, whereas the [3 isoform couples preferentially to the cGMP pathway. Coupling differences may be explained by the fact that five of the six amino acid substitutions between the two isoforms are localized within intracellular receptor regions potentially involved in G protein coupling. Allelic isoforms were also observed for Mel l a receptors expressed in ovine pars tuberalis, suggesting that polymorphism is a general feature of the melatonin receptor family. We also evaluated the potential of the two human melatonin receptor subtypes, Mel l and Mel l b, to modulate the cGMP pathway. Melatonin inhibited intracellular cGMP levels in a dose-dependent manner in HEK293 cells transfected with the human Mel l b receptor. This was not the case for HEK293 cells transfected with the human Mel1 a receptor. In conclusion, our results indicate that the expression of receptor subtypes and isoforms may permit differential signalling between melatonin receptors. © Inra/Elsevier, Paris melatonin receptor / polymorphism / signalling Rsum ― Polymorphisme et signalisation des rcepteurs de la mlatonine. Les rcepteurs de la mlatonine appartiennent la super-famille des rcepteurs coupls aux protines G. Le clonage des rcepteurs Mel 1 exprims dans la peau de xnope a rvl l'existence d'un polymorphisme de ces rcepteurs. L'expression htrologue de deux isoformes allliques, nommes Mel l c(a) et Me)ic(p), a indiqu des diffrences fonctionnelles dans leur proprits de signalisation. Les deux isoformes sont couples aux voies de l'AMPc et du GMP C . Nanmoins, l'isoforme a est couple prfrentiellement la voie de l'AMPc alors que l'isoforme (3 l'est celle du GMPc. Les diffrences de couplage peuvent tre expliques par le fait que cinq des six substitutions d'acides amins entre les deux iso- formes sont localises au sein des rgions intracellulaires du rcepteur potentiellement impliques dans