Melatonin receptor 1B explained

Melatonin receptor 1B, also known as MTNR1B, is a protein that in humans is encoded by the MTNR1B gene.^{[1] [2]}

Function

This gene encodes the MT₂ protein, one of two high-affinity forms of a receptor for melatonin, the primary hormone secreted by the pineal gland. This gene product is an integral membrane protein that is a G-protein coupled, 7-transmembrane receptor. It is found primarily in the retina and brain; however, this detection requires RT-PCR. It is thought to participate in light-dependent functions in the retina and may be involved in the neurobiological effects of melatonin.^[1] Besides the brain and retina this receptor is expressed on the bone forming cells where it regulates their function in depositing bone.^[3]

Clinical significance

Several studies have identified MTNR1B receptor mutations that are associated with increased average blood sugar level and around a 20 percent elevated risk of developing type 2 diabetes.^{[4] [5] [6]} MTNR1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in beta cells in islets.

Ligands

The following MT2R ligands have selectivity over MT1R:

• Compound 3d: antagonist with sub-nM affinity^[7]
• Compound 18f: antagonist and compound 18g partial agonist: sub-nM affinity, >100-fold selectivity over MT1^[8]
• Compound 14: antagonist^[9]
• Compound 13: agonist^[10]

See also

• Melatonin receptor
• Discovery and development of melatonin receptor agonists

Further reading

• Brzezinski A . Melatonin in humans . The New England Journal of Medicine . 336 . 3 . 186–95 . Jan 1997 . 8988899 . 10.1056/NEJM199701163360306 .
• 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 Mel1b melatonin receptor . Proceedings of the National Academy of Sciences of the United States of America . 92 . 19 . 8734–8 . Sep 1995 . 7568007 . 41041 . 10.1073/pnas.92.19.8734 . 1995PNAS...92.8734R . free .
• Reppert SM, Weaver DR, Ebisawa T, Mahle CD, Kolakowski LF . Cloning of a melatonin-related receptor from human pituitary . FEBS Letters . 386 . 2–3 . 219–24 . May 1996 . 8647286 . 10.1016/0014-5793(96)00437-1 . 38587331 . free .
• Niles LP, Wang J, Shen L, Lobb DK, Younglai EV . Melatonin receptor mRNA expression in human granulosa cells . Molecular and Cellular Endocrinology . 156 . 1–2 . 107–10 . Oct 1999 . 10612428 . 10.1016/S0303-7207(99)00135-5 . 42730113 .
• Ebisawa T, Uchiyama M, Kajimura N, Kamei Y, Shibui K, Kim K, Kudo Y, Iwase T, Sugishita M, Jodoi T, Ikeda M, Ozeki Y, Watanabe T, Sekimoto M, Katoh M, Yamada N, Toyoshima R, Okawa M, Takahashi K, Yamauchi T . Genetic polymorphisms of human melatonin 1b receptor gene in circadian rhythm sleep disorders and controls . Neuroscience Letters . 280 . 1 . 29–32 . Feb 2000 . 10696804 . 10.1016/S0304-3940(99)00981-7 . 24900890 .
• Roy D, Angelini NL, Fujieda H, Brown GM, Belsham DD . Cyclical regulation of GnRH gene expression in GT1-7 GnRH-secreting neurons by melatonin . Endocrinology . 142 . 11 . 4711–20 . Nov 2001 . 11606436 . 10.1210/endo.142.11.8464 . free .
• Ayoub MA, Couturier C, Lucas-Meunier E, Angers S, Fossier P, Bouvier M, Jockers R . Monitoring of ligand-independent dimerization and ligand-induced conformational changes of melatonin receptors in living cells by bioluminescence resonance energy transfer . The Journal of Biological Chemistry . 277 . 24 . 21522–8 . Jun 2002 . 11940583 . 10.1074/jbc.M200729200 . free .
• Yuan L, Collins AR, Dai J, Dubocovich ML, Hill SM . MT(1) melatonin receptor overexpression enhances the growth suppressive effect of melatonin in human breast cancer cells . Molecular and Cellular Endocrinology . 192 . 1–2 . 147–56 . Jun 2002 . 12088876 . 10.1016/S0303-7207(02)00029-1 . 54393974 .
• Slominski A, Pisarchik A, Zbytek B, Tobin DJ, Kauser S, Wortsman J . Functional activity of serotoninergic and melatoninergic systems expressed in the skin . Journal of Cellular Physiology . 196 . 1 . 144–53 . Jul 2003 . 12767050 . 10.1002/jcp.10287 . 24534729 . free .
• Ayoub MA, Levoye A, Delagrange P, Jockers R . Preferential formation of MT1/MT2 melatonin receptor heterodimers with distinct ligand interaction properties compared with MT2 homodimers . Molecular Pharmacology . 66 . 2 . 312–21 . Aug 2004 . 15266022 . 10.1124/mol.104.000398 . 39243124 .
• Mazna P, Berka K, Jelinkova I, Balik A, Svoboda P, Obsilova V, Obsil T, Teisinger J . Ligand binding to the human MT2 melatonin receptor: the role of residues in transmembrane domains 3, 6, and 7 . Biochemical and Biophysical Research Communications . 332 . 3 . 726–34 . Jul 2005 . 15913560 . 10.1016/j.bbrc.2005.05.017 .
• Ha E, Choe BK, Jung KH, Yoon SH, Park HJ, Park HK, Yim SV, Chung JH, Bae HS, Nam M, Baik HH, Hong SJ . Positive relationship between melatonin receptor type 1B polymorphism and rheumatoid factor in rheumatoid arthritis patients in the Korean population . Journal of Pineal Research . 39 . 2 . 201–5 . Sep 2005 . 16098099 . 10.1111/j.1600-079X.2005.00237.x . 9980281 .
• Savaskan E, Jockers R, Ayoub M, Angeloni D, Fraschini F, Flammer J, Eckert A, Müller-Spahn F, Meyer P . The MT2 melatonin receptor subtype is present in human retina and decreases in Alzheimer's disease . . 4 . 1 . 47–51 . Feb 2007 . 17316165 . 10.2174/156720507779939823 .
• Suzuki S, Masui Y, Ohnuki M, Miyakoda G, Mori T, Nakajima K, Sato M . Induction of metallothionein synthesis by cilostazol in mice and in human cultured neuronal cell lines . Biological & Pharmaceutical Bulletin . 30 . 4 . 791–4 . Apr 2007 . 17409522 . 10.1248/bpb.30.791 . free .
• Qiu XS, Tang NL, Yeung HY, Lee KM, Hung VW, Ng BK, Ma SL, Kwok RH, Qin L, Qiu Y, Cheng JC . Melatonin receptor 1B (MTNR1B) gene polymorphism is associated with the occurrence of adolescent idiopathic scoliosis . Spine . 32 . 16 . 1748–53 . Jul 2007 . 17632395 . 10.1097/BRS.0b013e3180b9f0ff . 6777367 .

External links

• Web site: Melatonin Receptors: MT₂ . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2008-12-05 . 2016-03-03 . https://web.archive.org/web/20160303195311/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2361 . dead .

Notes and References

1. Web site: Entrez Gene: MTNR1B melatonin receptor 1B.
2. 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 Mel1b melatonin receptor . Proceedings of the National Academy of Sciences of the United States of America . 92 . 19 . 8734–38 . Sep 1995 . 7568007 . 41041 . 10.1073/pnas.92.19.8734 . 1995PNAS...92.8734R . free .
3. Sharan K, Lewis K, Furukawa T, Yadav VK . Regulation of bone mass through pineal-derived melatonin-MT2 pathway . . 79A . 2 . 263–270 . 28512916 . 5575491 . 10.1111/jpi.12423. 2006 .
4. Web site: Gene That Regulates Glucose Levels And Increases Risk For Diabetes Identified . 2008-06-28 . ScienceDaily . 2009-01-18.

   Web site: Body Clock Linked To Diabetes And High Blood Sugar In New Genome-wide Study . 2008-12-08 . ScienceDaily . 2009-01-18. ; Web site: Is There A Relationship Between Sleep-wake Rhythm And Diabetes? A New Gene Variant Influences Fasting Glucose Levels Via The Melatonin Metabolism . 2009-01-16 . ScienceDaily . 2009-01-18.

5. Prokopenko I, Langenberg C, Florez JC, Saxena R, Soranzo N, Thorleifsson G, Loos RJ, Manning AK, Jackson AU, Aulchenko Y, Potter SC, Erdos MR, Sanna S, Hottenga JJ, Wheeler E, Kaakinen M, Lyssenko V, Chen WM, Ahmadi K, Beckmann JS, Bergman RN, Bochud M, Bonnycastle LL, Buchanan TA, Cao A, Cervino A, Coin L, Collins FS, Crisponi L, de Geus EJ, Dehghan A, Deloukas P, Doney AS, Elliott P, Freimer N, Gateva V, Herder C, Hofman A, Hughes TE, Hunt S, Illig T, Inouye M, Isomaa B, Johnson T, Kong A, Krestyaninova M, Kuusisto J, Laakso M, Lim N, Lindblad U, Lindgren CM, McCann OT, Mohlke KL, Morris AD, Naitza S, Orrù M, Palmer CN, Pouta A, Randall J, Rathmann W, Saramies J, Scheet P, Scott LJ, Scuteri A, Sharp S, Sijbrands E, Smit JH, Song K, Steinthorsdottir V, Stringham HM, Tuomi T, Tuomilehto J, Uitterlinden AG, Voight BF, Waterworth D, Wichmann HE, Willemsen G, Witteman JC, Yuan X, Zhao JH, Zeggini E, Schlessinger D, Sandhu M, Boomsma DI, Uda M, Spector TD, Penninx BW, Altshuler D, Vollenweider P, Jarvelin MR, Lakatta E, Waeber G, Fox CS, Peltonen L, Groop LC, Mooser V, Cupples LA, Thorsteinsdottir U, Boehnke M, Barroso I, Van Duijn C, Dupuis J, Watanabe RM, Stefansson K, McCarthy MI, Wareham NJ, Meigs JB, Abecasis GR . 6 . Variants in MTNR1B influence fasting glucose levels . Nature Genetics . 41 . 1 . 77–81 . Jan 2009 . 19060907 . 2682768 . 10.1038/ng.290 .

   Lyssenko V, Nagorny CL, Erdos MR, Wierup N, Jonsson A, Spégel P, Bugliani M, Saxena R, Fex M, Pulizzi N, Isomaa B, Tuomi T, Nilsson P, Kuusisto J, Tuomilehto J, Boehnke M, Altshuler D, Sundler F, Eriksson JG, Jackson AU, Laakso M, Marchetti P, Watanabe RM, Mulder H, Groop L . 6 . Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion . Nature Genetics . 41 . 1 . 82–88 . Jan 2009 . 19060908 . 10.1038/ng.288 . 3725650 . ; Bouatia-Naji N, Bonnefond A, Cavalcanti-Proença C, Sparsø T, Holmkvist J, Marchand M, Delplanque J, Lobbens S, Rocheleau G, Durand E, De Graeve F, Chèvre JC, Borch-Johnsen K, Hartikainen AL, Ruokonen A, Tichet J, Marre M, Weill J, Heude B, Tauber M, Lemaire K, Schuit F, Elliott P, Jørgensen T, Charpentier G, Hadjadj S, Cauchi S, Vaxillaire M, Sladek R, Visvikis-Siest S, Balkau B, Lévy-Marchal C, Pattou F, Meyre D, Blakemore AI, Jarvelin MR, Walley AJ, Hansen T, Dina C, Pedersen O, Froguel P . 6 . A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk . Nature Genetics . 41 . 1 . 89–94 . Jan 2009 . 19060909 . 10.1038/ng.277 . 205347673 .

6. Staiger H, Machicao F, Schäfer SA, Kirchhoff K, Kantartzis K, Guthoff M, Silbernagel G, Stefan N, Häring HU, Fritsche A . Polymorphisms within the novel type 2 diabetes risk locus MTNR1B determine beta-cell function . PLOS ONE . 3 . 12 . e3962 . 2008 . 19088850 . 2597741 . 10.1371/journal.pone.0003962 . 2008PLoSO...3.3962S . Maedler . Kathrin . free .
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