Characterization of the Mel1c melatoninergic receptor in platypus (Ornithorhynchus anatinus)

Abstract

Melatonin is a neurohormone produced in both animals and plants. It binds at least three G-protein-coupled receptors: MT1 and MT2, and Mel1cGPR. Mammalian GPR50 evolved from the reptilian/avian Mel1c and lost its capacity to bind melatonin in all the therian mammal species that have been tested. In order to determine if binding is lost in the oldest surviving mammalian lineage of monotremes we investigated whether the melatonin receptor has the ability to bind melatonin in the platypus (Ornithorhynchus anatinus), and evaluated its pharmacological profile. Sequence and phylogenetic analysis showed that platypus has in fact retained the ancestral Mel1c and has the capacity to bind melatonin similar to other mammalian melatonin receptors (MT1 and MT2), with an affinity in the 1 nM range. We also investigated the binding of a set of melatoninergic ligands used previously to characterize the molecular pharmacology of the melatonin receptors from sheep, rats, mice, and humans and found that the general profiles of these compounds make Mel1c resemble human MT1 more than MT2. This work shows that the loss of GPR50 binding evolved after the divergence of monotremes less than 190MYA in therian mammals.

Melatonin receptors in Atlantic salmon stimulate cAMP levels in heterologous cell lines and show season‐dependent daily variations in pituitary expression levels

“…Mtnr activates different intracellular signalling pathways, including the cAMP/PKA pathway, via G i proteins that inhibit adenylyl cyclase and subsequently cAMP formation (Mtnr1A and Mtnr1B), the PLC/PKC pathway via G q ‐proteins (Mtnr1A and Mtnr1C) and the cGMP pathway (Mtnr1B) . In therian mammals, Mtnr1C has lost the ability to respond to melatonin …”

“…12 In therian mammals, Mtnr1C has lost the ability to respond to melatonin. 13,14 Melatonin has widespread effects, as evidenced by the broad distribution of Mtnr in vertebrate nervous and peripheral tissues. 15 Of special interest to the present paper is the pituitary, where Mtnr expression has been detected in the pituitary pars tuberalis of mammals.…”

The five dimensions of receptor pharmacology exemplified by melatonin receptors: An opinion

“…In the melatonin receptor family, an orphan receptor has been identified; it is known as GPR50 (previously known as melatonin‐related receptor, MRR). Despite its family resemblance, it lacks any capacity to bind melatonin in mammals (except in platypus), and it is closely related to Mel1c, the third melatonin receptor found in batrachians and birds . However, it remains unknown whether GPCR heterodimers are physiologically relevant …”

“…Despite its family resemblance, it lacks any capacity to bind melatonin in mammals (except in platypus), 71 and it is closely related to Mel1c, the third melatonin receptor found in batrachians and birds. 71,72 However, it remains unknown whether GPCR heterodimers are physiologically relevant. 73 Understanding homodimerization has made it possible to synthesize and characterize homodimeric ligands 74,75 that can act as potent antagonists, as previously described for melatonin receptors.…”

Characterization of the various functional pathways elicited by synthetic agonists or antagonists at the melatonin MT1 and MT2 receptors

“…Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that regulates various biological functions in mammals through three different G protein-coupled receptors (GPCRs): MT 1 , MT 2 , and GPR50/Mel1c as reviewed by Jockers et al 1 However, GPR50 lost its capacity to bind melatonin during evolution, except in the case of the platypus, in which Mel1c binds melatonin. 2 Melatonin is also an effective pleiotropic agent in plants. 3 In mammals, melatonin regulates blood pressure, circadian entrainment, retinal physiology, oncogenesis, seasonal reproduction, ovarian physiology, and osteoblast differentiation, among other functions.…”