Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Melatonin Receptor MT1 and MT2

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101751


Historical Background

Melatonin (N-acetyl-5-methoxytryptamine) is an evolutionary old molecule which is derived from the essential amino acid tryptophan in a four-step biosynthesis pathway. Melatonin is synthesized by many organisms as diverse as bacteria, protists, fungi, macroalgae, plants, and animals. During evolution, several functions of melatonin appeared including protection of cells against oxidative stress, regulation of circadian rhythmicity, and ciliary swimming in invertebrates. The function of melatonin further expanded in mammals (see below). In mammals, the synthesis of melatonin is regulated by light and by the circadian activity of the biological clock located in the hypothalamic suprachiasmatic nuclei. Melatonin has been first isolated and its structure elucidated by Lerner et al. in 1959 (Lerner et al. 1959a, b). The first melatonin receptor has been identified in 1994 from a Xenopus laevis cDNA library by expression cloning (Ebisawa et al. 1994) followed by the cloning of two further receptor types called MT1 and MT2 (Reppert et al. 1994, 1995). MT1 knockout mice were first reported in 1997 (Liu et al. 1997) and MT2 knockout mice in 2003 (Jin et al. 2003) and contributed largely in the dissection of the specific roles of each receptor types and in the identification of new functions for melatonin receptors (Tosini et al. 2014). Pharmacological characterization of melatonin receptors led to the synthesis of many synthetic melatonin receptor ligands of which some are now commercially available as therapeutic drugs.

General Information on Melatonin Receptors (Sequence Homology, Structural Features, Expression Profile, and Signaling Properties)

Melatonin receptors belong to the 7-transmembrane class A G-protein-coupled receptor (GPCR) superfamily. The melatonin receptor subfamily consists of three members, MT1 and MT2 receptors (also called Mel1a and Mel1b, respectively, in nonmammals), both binding melatonin with high affinity, and GPR50 (homologous to Mel1c in nonmammals). Whereas Mel1c binds melatonin with high affinity, GPR50 has lost its ability to bind melatonin. Its expression was conserved during evolution, most likely due to melatonin-independent functions. GPR50/Mel1c will not be further considered here.

Human MT1 is composed of 350 amino acids (MTNR1A gene located at 4q35.1) and human MT2 of 362 amino acids (MTNR1B gene located at 11q21-q22), with 55% overall amino acid homology and 70% within transmembrane domains. Distinctive amino acid motifs of MT1 and MT2 are the 3.49NRY3.51 motif (instead of the well-conserved 3.49DRY3.51 motif) and the 7.49NPXXY7.53 motif (instead of the 7.49NAIXY7.53motif) (Zlotos et al. 2014; Liu et al. 2016) (Fig. 1). Currently no crystal structure of MT1 or MT2 is available.
Melatonin Receptor MT1 and MT2, Fig. 1

Topology of MT1 (a) and MT2 (b) receptor. Conserved motifs that are unique for the melatonin receptor subfamily are highlighted in yellow. Residues with blue circle are suspected to be directly involved in melatonin binding. Residues for which natural variants were identified are highlighted with a red circle

MT1 and MT2 are expressed in the brain, including the suprachiasmatic nuclei, in the pituitary and pineal glands, the retina, and several peripheral tissues (the liver, adipose tissue, pancreas, kidney, etc.) and some cancer cells (for more details, see Table 1).
Melatonin Receptor MT1 and MT2, Table 1

Expression profile of human MT1 and MT2 (information extracted from IUPHAR website (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=39)





Cerebellum, occipital cortex, parietal cortex, temporal cortex, thalamus, frontal cortex, hippocampus, suprachiasmatic nucleus

Cerebellum, hippocampus, suprachiasmatic nucleus

Peripheral tissue

Retina, brown and white adipose tissue, fetal kidney, coronary artery, granulosa cells

Retina, brown and white adipose tissue, fetal kidney, granulosa cells, uveal melanocytes and melanoma cells, placental tissues, PAZ6 brown adipocytes cell line, choriocarcinoma cell lines

Coupling of MT1 and MT2 to Gi/o proteins has been shown in many tissues. Coupling to Gq/11 proteins has been reported for MT1 in some tissues. MT1 and MT2 also associate with β-arrestin1/2. Downstream effector pathways include the ERK1/2, PI3K/AKT, and PKC/PLCß pathways as well as calcium-activated potassium channels (BKCa) and Kir3 inward-rectifier potassium channels, which have been reported to be activated, and adenylate and soluble guanylate cyclases, which have been reported to be inhibited by endogenously expressed melatonin receptors (Fig. 2) (Tosini et al. 2014).
Melatonin Receptor MT1 and MT2, Fig. 2

Signaling pathways modulated by MT1 (a), MT1/MT2 (b), and MT2 (c) receptors

MT1 and MT2 have been shown to form homodimers (MT1/MT1 or MT2/MT2) and heterodimers (MT1/MT2) in vitro and in vivo, in retinal photoreceptor cells (Ayoub et al. 2002; Baba et al. 2013). MT1 and MT2 form also heterodimers with GPR50. In the MT1/GPR50 heterodimer, melatonin binding to MT1 is abolished (Levoye et al. 2006). MT2 also heterodimerizes with serotonin 5-HT2C receptors. These heterodimers are putative targets of the antidepressant agomelatine (Kamal et al. 2015).

Melatonin Receptor Ligands

The cognate ligand of MT1 and MT2 is melatonin, which is present in various organisms. In mammals, the neurohormone melatonin is primarily synthesized during the night by the pineal gland and immediately secreted into the blood circulation (half-life 20–30 min). Serum melatonin concentrations are in the low pM to low nM range. The circulating melatonin is metabolized in the liver. Melatonin is also produced from other organs like the retina, the gastrointestinal tract, and the innate immune system. Pharmacologically, 4P–PDOT and luzindole are considered as gold standards of MT2 selective and MT1-MT2 nonselective antagonists, respectively. The full range of synthetic ligands for MT1 and MT2 were described in detail recently (Zlotos et al. 2014; Jockers et al. 2016). MT1 selective ligands are still missing.

Physiological Functions of Melatonin Receptors

Pharmacological activation or inhibition of melatonin receptors with subtype selective or non-selective ligands, targeted gene deletion in mice and suppression of endogenous melatonin production in constant light conditions were instrumental in understanding the physiological role of melatonin receptors (Tosini et al. 2014). Endogenous nighttime melatonin affects sleep onset and architecture, retinal functions (i.e. photoreceptor sensitivity), glucose homeostasis, immune functions, and seasonal reproduction, and the most extensively studied function of melatonin, the regulation of circadian rhythms (Dubocovich et al. 2010). Melatonin is also known to have anti-oxidant effects, which might be melatonin receptor dependent or independent (Jockers et al. 2016).

Role of Melatonin Receptors in Diseases and Therapy

Dysfunction of the melatonin receptor signal is often associated with sleep and circadian dysfunction and depression. Currently therapeutic application of melatonin and melatonin receptor agonists has been used quite commonly for circadian disorders such as jet lag, shift work, delayed-sleep and advanced-sleep phase syndrome, seasonal affective and non-24-h sleep-wake disorders, and major depression. A slow-release melatonin preparation/Circadin® (indication: insomnia in the elderly) and three nonselective MT1-MT2 synthetic agonists, ramelteon/Rozerem® (indication: insomnia), agomelatine/Valdoxan® (indication: major depressive disorder) and tasimelteon/Hetlioz® (indication: non-24-h sleep-wake disorder in totally blind individuals) are clinically available (Table 2). Agomelatine is also an antagonist for 5-HT2C receptors. In the United States of America and other countries, melatonin is commercially available as a supplement without prescription (Liu et al. 2016).
Melatonin Receptor MT1 and MT2, Table 2

Currently approved and frequently used ligands for melatonin receptors (Liu et al. 2016)


Affinity (Ki)

hMT1 (nM)

hMT2 (nM)

5HT2c (nM)


Circadin® (Neurin)



No effect


Rozerem® (Takeda)



No effect


Hetlioz® (Vanda)



No effect


Valdoxan® (Servier)












Potential further fields of application of melatonin-based therapies are type 2 diabetes, retinal diseases, neurodegenerative diseases (Alzheimer disease, Parkinson disease, Huntington disease), autism spectrum disorders, drug abuse, and some cancers (Tosini et al. 2014). Several common and rare variants have been identified in the MTNR1A and MTNR1B genes (Fig. 1). Rare loss-of-function MT2 mutants are associated with a five to sixfold increased risk for type 2 diabetes (Bonnefond et al. 2012).


Receptors for the neurohormone melatonin have been identified in fishes, birds, amphibians, and mammals. In humans, two melatonin receptors, called MT1 and MT2, bind melatonin with sub-nanomolar affinity to regulate various neuronal, retinal, immunological, and metabolic functions. A particular feature of the melatonin system in mammals is the circadian secretion pattern of melatonin with peak levels during the night and the capacity of its receptors to regulate the biological master clock located in the hypothalamus. Twenty years of medicinal chemistry generated a high diversity of chemical ligands targeting melatonin receptors, of which several are now available on the market to treat melatonin-related diseases such as insomnia, major depression, and non-24-h sleep-wake disorders.



We would like to acknowledge Dr. Erika Cecon for reading the manuscript and helpful suggestions.

This work was supported by the Fondation de la Recherche Médicale (Equipe FRM DEQ20130326503), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS) and the “Who am I?” laboratory of excellence No.ANR-11-LABX-0071 funded by the French Government through its “Investments for the Future” program operated by the French National Research Agency (ANR) under grant No.ANR-11-IDEX-0005-01.


  1. Ayoub MA, Couturier C, Lucas-Meunier E, Angers S, Fossier P, Bouvier M, et al. Monitoring of ligand-independent dimerization and ligand-induced conformational changes of melatonin receptors in living cells by bioluminescence resonance energy transfer. J Biol Chem. 2002;277:21522–8. doi:10.1074/jbc.M200729200.PubMedCrossRefGoogle Scholar
  2. Baba K, Benleulmi-Chaachoua A, Journe AS, Kamal M, Guillaume JL, Dussaud S, et al. Heteromeric MT1/MT2 melatonin receptors modulate photoreceptor function. Sci Signal. 2013;6:ra89. doi:10.1126/scisignal.2004302.PubMedCrossRefGoogle Scholar
  3. Bonnefond A, Clement N, Fawcett K, Yengo L, Vaillant E, Guillaume JL, et al. Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes. Nat Genet. 2012;44:297–301. doi:10.1038/ng.1053.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Dubocovich ML, Delagrange P, Krause DN, Sugden D, Cardinali DP, Olcese J. International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors. Pharmacol Rev. 2010;62:343–80.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Ebisawa T, Karne S, Lerner MR, Reppert SM. Expression cloning of a high-affinity melatonin receptor from Xenopus dermal melanophores. Proc Natl Acad Sci U S A. 1994;91:6133–7.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Jin X, von Gall C, Pieschl RL, Gribkoff VK, Stehle JH, Reppert SM, et al. Targeted disruption of the mouse Mel(1b) melatonin receptor. Mol Cell Biol. 2003;23:1054–60.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Jockers R, Delagrange P, Dubocovich ML, Markus RP, Renault N, Tosini G, et al. Update on melatonin receptors. IUPHAR Review. Br J Pharmacol. 2016. doi:10.1111/bph.13536.PubMedPubMedCentralGoogle Scholar
  8. Kamal M, Gbahou F, Guillaume JL, Daulat AM, Benleulmi-Chaachoua A, Luka M, et al. Convergence of melatonin and serotonin (5-HT) signaling at MT2/5-HT2C receptor heteromers. J Biol Chem. 2015;290:11537–46. doi:10.1074/jbc.M114.559542.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Lerner AB, Case JD, Biemann K, Heinzelman R, Szmuszkovicz J, Anthony W, et al. Isolation of 5-methoxyindole-3-acetic acid from bovine pineal glands. J Am Chem Soc. 1959a;81:5264. doi:10.1021/ja01528a064.CrossRefGoogle Scholar
  10. Lerner AB, Case JD, Heinzelman RV. Structure of melatonin. J Am Chem Soc. 1959b;81:6084–5. doi:10.1021/ja01531a060.CrossRefGoogle Scholar
  11. Levoye A, Dam J, Ayoub MA, Guillaume JL, Couturier C, Delagrange P, et al. The orphan GPR50 receptor specifically inhibits MT1 melatonin receptor function through heterodimerization. EMBO J. 2006;25:3012–23. doi:10.1038/sj.emboj.7601193.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Liu C, Weaver DR, Jin X, Shearman LP, Pieschl RL, Gribkoff VK, et al. Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron. 1997;19:91–102.PubMedCrossRefGoogle Scholar
  13. Liu J, Clough SJ, Hutchinson AJ, Adamah-Biassi EB, Popovska-Gorevski M, Dubocovich ML. MT1 and MT2 melatonin receptors: a therapeutic perspective. Annu Rev Pharmacol Toxicol. 2016;56:361–83. doi:10.1146/annurev-pharmtox-010814-124742.PubMedCrossRefGoogle Scholar
  14. Reppert SM, Weaver DR, Ebisawa T. Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron. 1994;13:1177–85. doi: http://dx.doi.org/10.1016/0896-6273(94)90055-8.
  15. Reppert SM, Godson C, Mahle CD, Weaver DR, Slaugenhaupt SA, Gusella JF. Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel(1b) melatonin receptor. Proc Natl Acad Sci U S A. 1995;92:8734–8.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Tosini G, Owino S, Guillaume JL, Jockers R. Understanding melatonin receptor pharmacology: latest insights from mouse models, and their relevance to human disease. BioEssays : News Rev Mol Cell Dev Biol. 2014;36:778–87. doi:10.1002/bies.201400017.CrossRefGoogle Scholar
  17. Zlotos DP, Jockers R, Cecon E, Rivara S, Witt-Enderby PA. MT1 and MT2 melatonin receptors: ligands, models, oligomers, and therapeutic potential. J Med Chem. 2014;57:3161–85. doi:10.1021/jm401343c.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Institut Cochin, INSERM, U1016, CNRS 8104, Université Paris DescartesParisFrance