Melatonin receptors: Introduction


The hormone melatonin is mainly produced by the pineal gland following a circadian rhythm, with high levels during the subjective night. In some cases melatonin can also be produced by extra-pineal sites like in cells from the innate immune system in a non-circadian manner. Melatonin regulates a variety of physiological and neuroendocrine functions through activation of G protein-coupled melatonin receptors in target tissues [19,36,46,74,77].

The use of the radioligands [3H]melatonin and 2-[125I]iodomelatonin has led to the localization and characterization in native tissues of a number of putative melatonin binding sites with well-defined and distinct pharmacological profiles [19]. The first classification of putative melatonin receptors into ML1 and ML2 types was based on kinetic and pharmacological differences of 2-[125I]iodomelatonin binding [17]. The pharmacological profile (2-iodomelatonin > melatonin >> N-acetylserotonin) of 2-[125I]iodomelatonin binding to mammalian retina and pars tuberalis corresponds closely to that of the functional melatonin receptor characterized in rabbit retina [17-18,35,43,49,59]. By contrast the pharmacology (2-iodomelatonin > melatonin = N-acetylserotonin) of 2-[125I]iodomelatonin binding to hamster brain membranes was distinguished by N-acetylserotonin, which showed equal affinity with melatonin [17-18,35,43] and corresponds to the ML2 type.

Cloning studies have revealed two recombinant mammalian melatonin receptors - Mel1a and Mel1b, now termed MT1 and MT2 [56-59] both encoding 2-[125I]iodomelatonin binding sites showing the general pharmacology of the ML1 type [22,59]. These two definitive melatonin receptors were defined as unique entities on the basis of their molecular structure and chromosomal localization [6,56-59,66]. The human melatonin receptors, (h MT1 and h MT2) show 60% homology to each other at the amino acid (aa) level. The 3D structure of hMT1 and hMT2 have been solved in the inactive form [37,69]. They have distinct pharmacological profiles of partial agonist and antagonist binding affinities for 2-[125I]iodomelatonin and [3H]melatonin [10,18-19,22,29]. The ML2 2-[125I]iodomelatonin binding site (now termed MT3), was identified in washed hamster brain membranes and originally thought to be a GPCR [24-26,33,48]. A new site with the pharmacological characteristics of the MT3 2-[125I]-iodomelatonin binding site in cytoplasmic fractions was been identified with quinone reductase 2 [53]. Indeed, brain and kidney membranes from mice with genetic deletion of quinone reductase 2 lacked specific 2-[125I]iodomelatonin binding to MT3 binding sites [9,45]. Whether the MT3 binding sites in washed brain membranes and on quinone reductase are the same or different binding sites is still an open question. The MT3 site is no longer considered within IUPHAR classification of G protein-coupled melatonin receptors.

MT1 receptors

A number of non-selective melatonin receptor agonists and antagonists have been identified [13-14,19,28-33,60,68,76-77], which have been useful in the pharmacological characterization of melatonin receptors in native tissues [22]. Work carried out with recombinant h MT1 receptors led to the identification of various analogues as inverse agonists (e.g., luzindole, 4P-PDOT) on recombinant human receptors [10,23,70] and in native tissues [10,21,27,67,70].

MT1 receptors signal via inhibitory G proteins (Gαi and Gαo) leading to adenylate cyclase inhibition and possibly inositol phosphate stimulation in recombinant systems. However, characterization of MT1 melatonin receptors mediating signalling in native tissues have not been reported [18,34-35,43,49,61]. In certain native tissues (e.g. sheep pars tuberalis, rat cerebral and caudal arteries) melatonin responses are presumably mediated through activation of MT1 receptors. However, most of the evidence for the presence of this receptor is indirect (i.e. expression of specific mRNA; immunohistochemistry) [1,56-58,62-65], with the rat caudal artery being the only tissue where pharmacological characterization of this receptor has been reported [12,42,47,71-73]. Using mice with genetic deletion of the MT1 melatonin receptor the following functions for this receptor have been demonstrated a) Inhibition neuronal firing (suprachiasmatic nucleus, [44]), b) phase shift of onset of circadian rhythm of running wheel activity (MT1 KO mouse, [20]); c) regulation of photoperiodic information (pars tuberalis, [75]).

MT2 receptors; d) regulation of PI3K expression in the liver [54]; e) regulation of body weight and the leptin response by downregulating the leptin receptor [11].

Recently, a number of MT2 receptor-selective melatonin receptor agonists, partial agonists and antagonists have been identified [2,13,19,22,41,50,52,60,77]. In rabbit retina melatonin inhibits [3H]dopamine release through activation of an MT2 presynaptic heteroreceptor showing a pharmacological profile of partial agonists and antagonists (KB values) similar to that of the recombinant human MT2 receptor (Ki for inhibition of 2-[125I]iodomelatonin binding) [22]. The affinity and potency of various synthetic melatonin receptor agonists and antagonists in heterologous cell lines using cell based assays (e.g., forskolin-stimulated cAMP accumulation; [35S]GTPγS binding). The MT2 receptors can exhibit a constitutive, non melatonin-induced signaling activity in two cellular models of different origins, the Chinese hamster ovary cell line and Neuro2A, a neuroblastoma cell line [15]. Various inverse agonists (i.e. UCM 549, UCM 724, UCSF3384, UCSF7447) have been described [15,40,70].

Activation of human recombinant melatonin receptors inhibits cAMP and cGMP formation [55-56,58]. MT2 receptor expression by RT-PCR and in situ hybridization suggests that this receptor may be expressed in mammalian retina, selected brain areas and some arterial beds [23,44,56,72]. The availability of selective MT2 receptor antagonists (4P-PDOT, 4P-ADOT) has led to the identification of functional MT2 melatonin receptors in retina (inhibition of dopamine release) [22], in the circadian timing system (phase shifting of circadian rhythms) [20,44], and in rat caudal artery (vasodilation) [16,47]. Using mice with genetic deletion of the MT2 melatonin receptor the following functions for this receptor have been demonstrated: a) phase shift of the peak of the circadian rhythm of neuronal firing (suprachiasmatic nucleus; [20,44]); b) inhibition dopamine release (rabbit retina; [22]); ]); c) inhibition of insulin release (pancreatic islets; [51]); d) increased dopamine uptake in striatal synaptosomes and reduced sensitivity to amphetamine [7] and others.

Genome-wide association studies identified frequent variants upstream of exon 1 or within the single intron of the MTNR1B gene coding for the MT2 receptor that associated with increased fasting plasma glucose levels and type 2 diabetes risk [39]. Exon sequencing revealed multiple rare variants of the MTNR1B gene wih loss-of-function phenotype associated with type 2 diabetes risk [8,38].

MT1/MT2 heteromers

GPCRs MT1 and MT2 receptors exist typically as monomers and homomers (di-, oligomers) when expressed individually. When expressed in the same cell MT1 and MT2 receptors have been shown to form also MT1/MT2 heteromers. This has been first shown in vitro [3-4] and then in vivo in retinal photoreceptor cells where they mediated the effect of melatonin on light sensitivity of rod photoreceptors in mice [5]. This effect of melatonin involved activation of the heteromer-specific phospholipase C and protein kinase C (PLC/PKC) pathway and was abolished in MT1 KO or MT2 KO mice, as well as in mice overexpressing a nonfunctional MT2 mutant that interfered with the formation of functional MT1/MT2 heteromers in photoreceptor cells. A leftward shift of the EC50 value of inhibition of cAMP production by melatonin was observed in cells expressing MT1/MT2 heteromers as compared to the corresponding homomers in transfected HEK293 cells.


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