Alternative titles; symbols
HGNC Approved Gene Symbol: MTNR1A
Cytogenetic location: 4q35.2 Genomic coordinates (GRCh38): 4:186,533,655-186,555,567 (from NCBI)
Melatonin, the principal hormone of the pineal gland, functions through pharmacologically specific, G protein-coupled receptors. Melatonin can alter the timing of mammalian circadian rhythms, as well as regulate the reproductive alterations that occur in response to changes in day length in seasonally breeding mammals. The circadian effects of melatonin appear to be mediated by melatonin receptors in the hypothalamic suprachiasmatic nucleus, the site of a circadian clock. The reproductive effects of melatonin may be mediated by receptors in the hypophyseal pars tuberalis. MTNR1A is a high-affinity melatonin receptor that likely mediates these 2 major biologic functions of melatonin in mammals (Slaugenhaupt et al., 1995).
Reppert et al. (1994) cloned human MTNR1A. The deduced 350-amino acid protein has characteristics of a G protein-coupled receptor, including 7 transmembrane domains. Slaugenhaupt et al. (1995) noted that MTNR1A defines a novel group within the G protein-coupled receptor family because of distinguishing structural features.
Reppert et al. (1994) showed that expression of human MTNR1A in COS-7 cells resulted in high-affinity binding of radiolabeled melatonin with pharmacologic characteristics similar to endogenous high-affinity receptors. Functional studies of mouse fibroblasts stably expressing sheep Mtnr1a showed that the mammalian melatonin receptor is coupled to inhibition of adenylyl cyclase (see 103072) through a pertussis toxin-sensitive mechanism.
Sleep disruption, nightly restlessness, sundowning, and other circadian disturbances are frequently seen in Alzheimer disease (AD; 104300) patients. Since melatonin is the main endocrine message for circadian rhythmicity from the pineal, Liu et al. (1999) studied melatonin levels in the cerebrospinal fluid (CSF) of 85 AD patients and 82 age-matched controls. In old control subjects (older than 80 years of age), CSF melatonin levels were half those of control subjects 41 to 80 years of age. In AD patients the CSF melatonin levels were only one-fifth of those in control subjects. The authors did not find a diurnal rhythm in CSF melatonin levels in control subjects or AD patients.
Von Gall et al. (2002) demonstrated that cycling expression of the clock gene Period-1 (602260) in rodent pituitary cells depends on the heterologous sensitization of the adenosine A2B receptor (600446), which occurs through the nocturnal activation of melatonin mt1 receptors. Eliminating the impact of the neurohormone melatonin simultaneously suppresses the expression of Period-1 and evokes an increase in the release of pituitary prolactin. Von Gall et al. (2002) concluded that their observations expose a mechanism by which 2 convergent signals interact within a temporal dimension to establish high-amplitude, precise, and robust cycles of gene expression.
Nelson et al. (2001) created point mutations at residue asp124 in cytoplasmic domain II of the melatonin 1a receptor and expressed mutant receptors in a neurohormonal cell line. The acidic N124D- and E-substituted receptors had high-affinity melatonin binding and a subcellular localization similar to the neutral N124N wildtype receptor. Melatonin efficacy for the inhibition of cAMP by N124D and E mutations was significantly decreased. Mutants at N124 separated into 2 sets: the first bound melatonin with high affinity and trafficked normally, but with reduced inhibitory coupling to adenylyl cyclase and calcium channels. The second set lacked melatonin binding and exhibited severe trafficking defects. In summary, asp124 controls melatonin receptor function as evidenced by changes in melatonin binding, control of cAMP levels, and regulation of ion channel activity. Asp124 also has a unique structural effect controlling receptor distribution within the cell.
Levoye et al. (2006) noted that the melatonin receptors MTNR1A and MTNR1B (600804) share a high degree of sequence homology with GPR50 (300207). They showed that GPR50 heterodimerized with both melatonin receptors in vitro and in intact cells. Association of GPR50 with MTNR1B did not modify MTNR1B function, but association of GPR50 with MTNR1A abolished high-affinity agonist binding and G protein coupling to MTNR1A. Deletion of the large C-terminal tail of GPR50 suppressed the inhibitory effect of GPR50 on MTNR1A without affecting heterodimerization.
Reviews
Weaver et al. (1991) reviewed localization of melatonin receptors in mammalian brain.
Reppert and Weaver (1995) reviewed the hormonal properties of melatonin and the characteristics of the melatonin receptors.
Brzezinski (1997) gave a comprehensive review of the function of melatonin and its clinical implications.
Slaugenhaupt et al. (1995) stated that the coding region of the MTNR1A gene consists of 2 exons.
Crystal Structure
Stauch et al. (2019) presented high-resolution room-temperature X-ray free electron laser (XFEL) structures of MT1 in complex with 4 agonists: the insomnia drug ramelteon, 2 melatonin analogs, and the mixed melatonin-serotonin antidepressant agomelatine. Although MT1 and the 5-hydroxytryptamine (serotonin) receptor (HTR1A; 109760) have similar endogenous ligands, and agomelatine acts on both receptors, the receptors differ markedly in the structure and composition of their ligand pockets; in MT1, access to the ligand pocket is tightly sealed from solvent by extracellular loop 2, leaving only a narrow channel between transmembrane helices IV and V that connects it to the lipid bilayer. The binding site is extremely compact, and ligands interact with MT1 mainly by strong aromatic stacking with phe179 and auxiliary hydrogen bonds with asn162 and gln181.
Johansson et al. (2019) reported XFEL structures of the human MT2 receptor (MTNR1B; 600804) in complex with the agonists 2-phenylmelatonin and ramelteon at resolutions of 2.8 angstroms and 3.3 angstroms, respectively, along with 2 structures of function-related mutants: H208(5.46)A and N86(2.50)D, obtained in complex with 2-phenylmelatonin. Comparison of the structures of MT2 with a published structure of MT1 (Stauch et al., 2019) revealed that, despite conservation of the orthosteric ligand-binding site residues, there are notable conformational variations as well as differences in tritiated melatonin dissociation kinetics that provided insights into the selectivity between melatonin receptor subtypes. A membrane-buried lateral ligand entry channel was observed in both MT1 and MT2, but in addition the MT2 structures revealed a narrow opening towards the solvent in the extracellular part of the receptor. Johansson et al. (2019) provided functional and kinetic data that supported a prominent role for intramembrane ligand entry in both receptors, and suggested that there might also be an extracellular entry path in MT2.
To localize the MTNR1A gene, Slaugenhaupt et al. (1995) developed an intronic PCR assay that amplified only the human gene from a panel of 43 human/rodent somatic cell hybrids containing defined overlapping subsets of human chromosomes. In this way, the gene was mapped to chromosome 4; it was further localized to 4q35.1 by PCR of a panel of somatic cell hybrids containing various deletion fragments of human chromosome 4. By an interspecific backcross analysis, the mouse homolog, Mtnr1a, was mapped to the proximal portion of mouse chromosome 8. Slaugenhaupt et al. (1995) suggested that the MTNR1A locus may be involved in genetically based circadian and neuroendocrine disorders.
Brzezinski, A. Melatonin in humans. New Eng. J. Med. 336: 186-195, 1997. [PubMed: 8988899] [Full Text: https://doi.org/10.1056/NEJM199701163360306]
Johansson, L. C., Stauch, B., McCorvy, J. D., Han, G. W., Patel, N., Huang, X.-P., Batyuk, A., Gati, C., Slocum, S. T., Li, C., Grandner, J. M., Hao, S., and 12 others. XFEL structures of the human MT2 melatonin receptor reveal the basis of subtype selectivity. Nature 569: 289-292, 2019. [PubMed: 31019305] [Full Text: https://doi.org/10.1038/s41586-019-1144-0]
Levoye, A., Dam, J., Ayoub, M. A., Guillaume, J.-L., Couturier, C., Delagrange, P., Jockers, R. The orphan GPR50 receptor specifically inhibits MT1 melatonin receptor function through heterodimerization. EMBO J. 25: 3012-3023, 2006. [PubMed: 16778767] [Full Text: https://doi.org/10.1038/sj.emboj.7601193]
Liu, R.-Y., Zhou, J.-N., van Heerikhuize, J., Hofman, M. A., Swaab, D. F. Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer's disease, and apolipoprotein E-epsilon-4/4 genotype. J. Clin. Endocr. Metab. 84: 323-327, 1999. [PubMed: 9920102] [Full Text: https://doi.org/10.1210/jcem.84.1.5394]
Nelson, C. S., Ikeda, M., Gompf, H. S., Robinson, M. L., Fuchs, N. K., Yoshioka, T., Neve, K. A., Allen, C. N. Regulation of melatonin 1a receptor signaling and trafficking by asparagine-124. Molec. Endocr. 15: 1306-1317, 2001. [PubMed: 11463855] [Full Text: https://doi.org/10.1210/mend.15.8.0681]
Reppert, S. M., Weaver, D. R., Ebisawa, T. Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron 13: 1177-1185, 1994. [PubMed: 7946354] [Full Text: https://doi.org/10.1016/0896-6273(94)90055-8]
Reppert, S. M., Weaver, D. R. Melatonin madness. Cell 83: 1059-1062, 1995. [PubMed: 8548792] [Full Text: https://doi.org/10.1016/0092-8674(95)90131-0]
Slaugenhaupt, S. A., Roca, A. L., Liebert, C. B., Altherr, M. R., Gusella, J. F., Reppert, S. M. Mapping of the gene for the Mel1a-melatonin receptor to human chromosome 4 (MTNR1A) and mouse chromosome 8 (Mtnr1a). Genomics 27: 355-357, 1995. [PubMed: 7558006] [Full Text: https://doi.org/10.1006/geno.1995.1056]
Stauch, B., Johansson, L. C., McCorvy, J. D., Patel, N., Han, G. W., Huang, X. P., Gati, C., Batyuk, A., Slocum, S. T., Ishchenko, A., Brehm, W., White, T. A., and 15 others. Structural basis of ligand recognition at the human MT1 melatonin receptor. Nature 569: 284-288, 2019. Note: Erratum: Nature 569: E6, 2019. Electronic Article. [PubMed: 31019306] [Full Text: https://doi.org/10.1038/s41586-019-1141-3]
von Gall, C., Garabette, M. L., Kell, C. A., Frenzel, S., Dehghani, F., Schumm-Draeger, P.-M., Weaver, D. R., Korf, H.-W., Hastings, M. H., Stehle, J. H. Rhythmic gene expression in pituitary depends on heterologous sensitization by the neurohormone melatonin. Nature Neurosci. 5: 234-238, 2002. [PubMed: 11836530] [Full Text: https://doi.org/10.1038/nn806]
Weaver, D. R., Rivkees, S. A., Carlson, L. L., Reppert, S. M. Localization of melatonin receptors in mammalian brain.In: Klein, D. C.; Moore, R. Y.; Reppert, S. M. : Suprachiasmatic Nucleus: The Mind's Clock. New York: Oxford Press (pub.) 1991.