This gene encodes the MT2protein, 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.[5] Besides the brain and retina this receptor is expressed on the bone forming cells where it regulates their function in depositing bone.[7]
Clinical significanceedit
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.[8][9][10] MTNR1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in beta cells in islets.[9]
Ligandsedit
The following MT2R ligands have selectivity over MT1R:
^Reppert SM, Godson C, Mahle CD, Weaver DR, Slaugenhaupt SA, Gusella JF (Sep 1995). "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. Bibcode:1995PNAS...92.8734R. doi:10.1073/pnas.92.19.8734. PMC41041. PMID 7568007.
^Sharan K, Lewis K, Furukawa T, Yadav VK (2006). "Regulation of bone mass through pineal-derived melatonin-MT2 pathway". J Pineal Res. 79A (2): 263–270. doi:10.1111/jpi.12423. PMC5575491. PMID 28512916.
^"Gene That Regulates Glucose Levels And Increases Risk For Diabetes Identified". ScienceDaily. 2008-06-28. Retrieved 2009-01-18.; "Body Clock Linked To Diabetes And High Blood Sugar In New Genome-wide Study". ScienceDaily. 2008-12-08. Retrieved 2009-01-18.; "Is There A Relationship Between Sleep-wake Rhythm And Diabetes? A New Gene Variant Influences Fasting Glucose Levels Via The Melatonin Metabolism". ScienceDaily. 2009-01-16. Retrieved 2009-01-18.
^ abProkopenko I, Langenberg C, Florez JC, Saxena R, Soranzo N, Thorleifsson G, et al. (Jan 2009). "Variants in MTNR1B influence fasting glucose levels". Nature Genetics. 41 (1): 77–81. doi:10.1038/ng.290. PMC2682768. PMID 19060907.; Lyssenko V, Nagorny CL, Erdos MR, Wierup N, Jonsson A, Spégel P, et al. (Jan 2009). "Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion". Nature Genetics. 41 (1): 82–88. doi:10.1038/ng.288. PMC3725650. PMID 19060908.; Bouatia-Naji N, Bonnefond A, Cavalcanti-Proença C, Sparsø T, Holmkvist J, Marchand M, et al. (Jan 2009). "A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk". Nature Genetics. 41 (1): 89–94. doi:10.1038/ng.277. PMID 19060909. S2CID 205347673.
^Staiger H, Machicao F, Schäfer SA, Kirchhoff K, Kantartzis K, Guthoff M, Silbernagel G, Stefan N, Häring HU, Fritsche A (2008). Maedler K (ed.). "Polymorphisms within the novel type 2 diabetes risk locus MTNR1B determine beta-cell function". PLOS ONE. 3 (12): e3962. Bibcode:2008PLoSO...3.3962S. doi:10.1371/journal.pone.0003962. PMC2597741. PMID 19088850.
^Rivara S, Lodola A, Mor M, Bedini A, Spadoni G, Lucini V, Pannacci M, Fraschini F, Scaglione F, Sanchez RO, Gobbi G, Tarzia G (Dec 2007). "N-(substituted-anilinoethyl)amides: design, synthesis, and pharmacological characterization of a new class of melatonin receptor ligands". Journal of Medicinal Chemistry. 50 (26): 6618–26. doi:10.1021/jm700957j. hdl:11576/1886829. PMID 18052314.
^Bedini A, Spadoni G, Gatti G, Lucarini S, Tarzia G, Rivara S, Lorenzi S, Lodola A, Mor M, Lucini V, Pannacci M, Scaglione F (Dec 2006). "Design and synthesis of N-(3,3-diphenylpropenyl)alkanamides as a novel class of high-affinity MT2-selective melatonin receptor ligands". Journal of Medicinal Chemistry. 49 (25): 7393–403. doi:10.1021/jm060850a. PMID 17149869.
^Yous S, Durieux-Poissonnier S, Lipka-Belloli E, Guelzim H, Bochu C, Audinot V, Boutin JA, Delagrange P, Bennejean C, Renard P, Lesieur D (Mar 2003). "Design and synthesis of 3-phenyl tetrahydronaphthalenic derivatives as new selective MT2 melatoninergic ligands". Bioorganic & Medicinal Chemistry. 11 (5): 753–59. doi:10.1016/S0968-0896(02)00473-X. PMID 12538005.
Brzezinski A (Jan 1997). "Melatonin in humans". The New England Journal of Medicine. 336 (3): 186–95. doi:10.1056/NEJM199701163360306. PMID 8988899.
Reppert SM, Godson C, Mahle CD, Weaver DR, Slaugenhaupt SA, Gusella JF (Sep 1995). "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. Bibcode:1995PNAS...92.8734R. doi:10.1073/pnas.92.19.8734. PMC41041. PMID 7568007.
Reppert SM, Weaver DR, Ebisawa T, Mahle CD, Kolakowski LF (May 1996). "Cloning of a melatonin-related receptor from human pituitary". FEBS Letters. 386 (2–3): 219–24. doi:10.1016/0014-5793(96)00437-1. PMID 8647286. S2CID 38587331.
Niles LP, Wang J, Shen L, Lobb DK, Younglai EV (Oct 1999). "Melatonin receptor mRNA expression in human granulosa cells". Molecular and Cellular Endocrinology. 156 (1–2): 107–10. doi:10.1016/S0303-7207(99)00135-5. PMID 10612428. S2CID 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 (Feb 2000). "Genetic polymorphisms of human melatonin 1b receptor gene in circadian rhythm sleep disorders and controls". Neuroscience Letters. 280 (1): 29–32. doi:10.1016/S0304-3940(99)00981-7. PMID 10696804. S2CID 24900890.
Roy D, Angelini NL, Fujieda H, Brown GM, Belsham DD (Nov 2001). "Cyclical regulation of GnRH gene expression in GT1-7 GnRH-secreting neurons by melatonin". Endocrinology. 142 (11): 4711–20. doi:10.1210/endo.142.11.8464. PMID 11606436.
Ayoub MA, Couturier C, Lucas-Meunier E, Angers S, Fossier P, Bouvier M, Jockers R (Jun 2002). "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. doi:10.1074/jbc.M200729200. PMID 11940583.
Yuan L, Collins AR, Dai J, Dubocovich ML, Hill SM (Jun 2002). "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. doi:10.1016/S0303-7207(02)00029-1. PMID 12088876. S2CID 54393974.
Slominski A, Pisarchik A, Zbytek B, Tobin DJ, Kauser S, Wortsman J (Jul 2003). "Functional activity of serotoninergic and melatoninergic systems expressed in the skin". Journal of Cellular Physiology. 196 (1): 144–53. doi:10.1002/jcp.10287. PMID 12767050. S2CID 24534729.
Ayoub MA, Levoye A, Delagrange P, Jockers R (Aug 2004). "Preferential formation of MT1/MT2 melatonin receptor heterodimers with distinct ligand interaction properties compared with MT2 homodimers". Molecular Pharmacology. 66 (2): 312–21. doi:10.1124/mol.104.000398. PMID 15266022. S2CID 39243124.
Mazna P, Berka K, Jelinkova I, Balik A, Svoboda P, Obsilova V, Obsil T, Teisinger J (Jul 2005). "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. doi:10.1016/j.bbrc.2005.05.017. PMID 15913560.
Ha E, Choe BK, Jung KH, Yoon SH, Park HJ, Park HK, Yim SV, Chung JH, Bae HS, Nam M, Baik HH, Hong SJ (Sep 2005). "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. doi:10.1111/j.1600-079X.2005.00237.x. PMID 16098099. S2CID 9980281.
Savaskan E, Jockers R, Ayoub M, Angeloni D, Fraschini F, Flammer J, Eckert A, Müller-Spahn F, Meyer P (Feb 2007). "The MT2 melatonin receptor subtype is present in human retina and decreases in Alzheimer's disease". Current Alzheimer Research. 4 (1): 47–51. doi:10.2174/156720507779939823. PMID 17316165.
Suzuki S, Masui Y, Ohnuki M, Miyakoda G, Mori T, Nakajima K, Sato M (Apr 2007). "Induction of metallothionein synthesis by cilostazol in mice and in human cultured neuronal cell lines". Biological & Pharmaceutical Bulletin. 30 (4): 791–4. doi:10.1248/bpb.30.791. PMID 17409522.
Qiu XS, Tang NL, Yeung HY, Lee KM, Hung VW, Ng BK, Ma SL, Kwok RH, Qin L, Qiu Y, Cheng JC (Jul 2007). "Melatonin receptor 1B (MTNR1B) gene polymorphism is associated with the occurrence of adolescent idiopathic scoliosis". Spine. 32 (16): 1748–53. doi:10.1097/BRS.0b013e3180b9f0ff. PMID 17632395. S2CID 6777367.
External linksedit
. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2016-03-03. Retrieved 2008-12-05.
melatonin, receptor, also, known, mtnr1b, protein, that, humans, encoded, mtnr1b, gene, mtnr1bidentifiersaliasesmtnr1b, fgqtl2, external, idsomim, 600804, 2181726, homologene, 4350, genecards, mtnr1bgene, location, human, chromosome, human, band11q14, 3start92. Melatonin receptor 1B also known as MTNR1B is a protein that in humans is encoded by the MTNR1B gene 5 6 MTNR1BIdentifiersAliasesMTNR1B FGQTL2 MEL 1B R MT2 Melatonin receptor 1BExternal IDsOMIM 600804 MGI 2181726 HomoloGene 4350 GeneCards MTNR1BGene location Human Chr Chromosome 11 human 1 Band11q14 3Start92 969 651 bp 1 End92 985 066 bp 1 Gene location Mouse Chr Chromosome 9 mouse 2 Band9 9 A2Start15 735 824 bp 2 End15 785 852 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inislet of Langerhansnucleus accumbensplacentacaudate nucleusrenal cortexendometriumhypothalamusprefrontal cortextemporal lobeurinary bladderTop expressed inlipMore reference expression dataBioGPSMore reference expression dataGene ontologyMolecular functionsignal transducer activity melatonin receptor activity protein binding G protein coupled receptor activityCellular componentintegral component of membrane membrane integral component of plasma membrane plasma membraneBiological processglucose homeostasis regulation of insulin secretion G protein coupled receptor signaling pathway coupled to cyclic nucleotide second messenger circadian rhythm signal transduction chemical synaptic transmission G protein coupled receptor signaling pathway negative regulation of cGMP mediated signaling positive regulation of circadian rhythm camera type eye development negative regulation of neuron apoptotic process positive regulation of circadian sleep wake cycle non REM sleep negative regulation of insulin secretion negative regulation of cytosolic calcium ion concentration negative regulation of transmission of nerve impulse positive regulation of transmission of nerve impulse regulation of neuronal action potential negative regulation of delayed rectifier potassium channel activitySources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez4544244701EnsemblENSG00000134640ENSMUSG00000050901UniProtP49286Q8CIQ6Q3SXF8RefSeq mRNA NM 005959NM 145712RefSeq protein NP 005950NP 663758Location UCSC Chr 11 92 97 92 99 MbChr 9 15 74 15 79 MbPubMed search 3 4 WikidataView Edit HumanView Edit Mouse Contents 1 Function 2 Clinical significance 3 Ligands 4 See also 5 References 6 Further reading 7 External linksFunction editThis 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 5 Besides the brain and retina this receptor is expressed on the bone forming cells where it regulates their function in depositing bone 7 Clinical significance editSeveral 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 8 9 10 MTNR1B mRNA is expressed in human islets and immunocytochemistry confirms that it is primarily localized in beta cells in islets 9 Ligands editThe following MT2R ligands have selectivity over MT1R Compound 3d antagonist with sub nM affinity 11 Compound 18f antagonist and compound 18g partial agonist sub nM affinity gt 100 fold selectivity over MT1 12 Compound 14 antagonist 13 Compound 13 agonist 14 See also editMelatonin receptor Discovery and development of melatonin receptor agonistsReferences edit a b c GRCh38 Ensembl release 89 ENSG00000134640 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000050901 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine a b Entrez Gene MTNR1B melatonin receptor 1B Reppert SM Godson C Mahle CD Weaver DR Slaugenhaupt SA Gusella JF Sep 1995 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 Bibcode 1995PNAS 92 8734R doi 10 1073 pnas 92 19 8734 PMC 41041 PMID 7568007 Sharan K Lewis K Furukawa T Yadav VK 2006 Regulation of bone mass through pineal derived melatonin MT2 pathway J Pineal Res 79A 2 263 270 doi 10 1111 jpi 12423 PMC 5575491 PMID 28512916 Gene That Regulates Glucose Levels And Increases Risk For Diabetes Identified ScienceDaily 2008 06 28 Retrieved 2009 01 18 Body Clock Linked To Diabetes And High Blood Sugar In New Genome wide Study ScienceDaily 2008 12 08 Retrieved 2009 01 18 Is There A Relationship Between Sleep wake Rhythm And Diabetes A New Gene Variant Influences Fasting Glucose Levels Via The Melatonin Metabolism ScienceDaily 2009 01 16 Retrieved 2009 01 18 a b Prokopenko I Langenberg C Florez JC Saxena R Soranzo N Thorleifsson G et al Jan 2009 Variants in MTNR1B influence fasting glucose levels Nature Genetics 41 1 77 81 doi 10 1038 ng 290 PMC 2682768 PMID 19060907 Lyssenko V Nagorny CL Erdos MR Wierup N Jonsson A Spegel P et al Jan 2009 Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion Nature Genetics 41 1 82 88 doi 10 1038 ng 288 PMC 3725650 PMID 19060908 Bouatia Naji N Bonnefond A Cavalcanti Proenca C Sparso T Holmkvist J Marchand M et al Jan 2009 A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk Nature Genetics 41 1 89 94 doi 10 1038 ng 277 PMID 19060909 S2CID 205347673 Staiger H Machicao F Schafer SA Kirchhoff K Kantartzis K Guthoff M Silbernagel G Stefan N Haring HU Fritsche A 2008 Maedler K ed Polymorphisms within the novel type 2 diabetes risk locus MTNR1B determine beta cell function PLOS ONE 3 12 e3962 Bibcode 2008PLoSO 3 3962S doi 10 1371 journal pone 0003962 PMC 2597741 PMID 19088850 Rivara S Lodola A Mor M Bedini A Spadoni G Lucini V Pannacci M Fraschini F Scaglione F Sanchez RO Gobbi G Tarzia G Dec 2007 N substituted anilinoethyl amides design synthesis and pharmacological characterization of a new class of melatonin receptor ligands Journal of Medicinal Chemistry 50 26 6618 26 doi 10 1021 jm700957j hdl 11576 1886829 PMID 18052314 Bedini A Spadoni G Gatti G Lucarini S Tarzia G Rivara S Lorenzi S Lodola A Mor M Lucini V Pannacci M Scaglione F Dec 2006 Design and synthesis of N 3 3 diphenylpropenyl alkanamides as a novel class of high affinity MT2 selective melatonin receptor ligands Journal of Medicinal Chemistry 49 25 7393 403 doi 10 1021 jm060850a PMID 17149869 Yous S Durieux Poissonnier S Lipka Belloli E Guelzim H Bochu C Audinot V Boutin JA Delagrange P Bennejean C Renard P Lesieur D Mar 2003 Design and synthesis of 3 phenyl tetrahydronaphthalenic derivatives as new selective MT2 melatoninergic ligands Bioorganic amp Medicinal Chemistry 11 5 753 59 doi 10 1016 S0968 0896 02 00473 X PMID 12538005 Mattson RJ Catt JD Keavy D Sloan CP Epperson J Gao Q Hodges DB Iben L Mahle CD Ryan E Yocca FD Mar 2003 Indanyl piperazines as melatonergic MT2 selective agents Bioorganic amp Medicinal Chemistry Letters 13 6 1199 202 doi 10 1016 S0960 894X 03 00090 8 PMID 12643943 Further reading editBrzezinski A Jan 1997 Melatonin in humans The New England Journal of Medicine 336 3 186 95 doi 10 1056 NEJM199701163360306 PMID 8988899 Reppert SM Godson C Mahle CD Weaver DR Slaugenhaupt SA Gusella JF Sep 1995 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 Bibcode 1995PNAS 92 8734R doi 10 1073 pnas 92 19 8734 PMC 41041 PMID 7568007 Reppert SM Weaver DR Ebisawa T Mahle CD Kolakowski LF May 1996 Cloning of a melatonin related receptor from human pituitary FEBS Letters 386 2 3 219 24 doi 10 1016 0014 5793 96 00437 1 PMID 8647286 S2CID 38587331 Niles LP Wang J Shen L Lobb DK Younglai EV Oct 1999 Melatonin receptor mRNA expression in human granulosa cells Molecular and Cellular Endocrinology 156 1 2 107 10 doi 10 1016 S0303 7207 99 00135 5 PMID 10612428 S2CID 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 Feb 2000 Genetic polymorphisms of human melatonin 1b receptor gene in circadian rhythm sleep disorders and controls Neuroscience Letters 280 1 29 32 doi 10 1016 S0304 3940 99 00981 7 PMID 10696804 S2CID 24900890 Roy D Angelini NL Fujieda H Brown GM Belsham DD Nov 2001 Cyclical regulation of GnRH gene expression in GT1 7 GnRH secreting neurons by melatonin Endocrinology 142 11 4711 20 doi 10 1210 endo 142 11 8464 PMID 11606436 Ayoub MA Couturier C Lucas Meunier E Angers S Fossier P Bouvier M Jockers R Jun 2002 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 doi 10 1074 jbc M200729200 PMID 11940583 Yuan L Collins AR Dai J Dubocovich ML Hill SM Jun 2002 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 doi 10 1016 S0303 7207 02 00029 1 PMID 12088876 S2CID 54393974 Slominski A Pisarchik A Zbytek B Tobin DJ Kauser S Wortsman J Jul 2003 Functional activity of serotoninergic and melatoninergic systems expressed in the skin Journal of Cellular Physiology 196 1 144 53 doi 10 1002 jcp 10287 PMID 12767050 S2CID 24534729 Ayoub MA Levoye A Delagrange P Jockers R Aug 2004 Preferential formation of MT1 MT2 melatonin receptor heterodimers with distinct ligand interaction properties compared with MT2 homodimers Molecular Pharmacology 66 2 312 21 doi 10 1124 mol 104 000398 PMID 15266022 S2CID 39243124 Mazna P Berka K Jelinkova I Balik A Svoboda P Obsilova V Obsil T Teisinger J Jul 2005 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 doi 10 1016 j bbrc 2005 05 017 PMID 15913560 Ha E Choe BK Jung KH Yoon SH Park HJ Park HK Yim SV Chung JH Bae HS Nam M Baik HH Hong SJ Sep 2005 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 doi 10 1111 j 1600 079X 2005 00237 x PMID 16098099 S2CID 9980281 Savaskan E Jockers R Ayoub M Angeloni D Fraschini F Flammer J Eckert A Muller Spahn F Meyer P Feb 2007 The MT2 melatonin receptor subtype is present in human retina and decreases in Alzheimer s disease Current Alzheimer Research 4 1 47 51 doi 10 2174 156720507779939823 PMID 17316165 Suzuki S Masui Y Ohnuki M Miyakoda G Mori T Nakajima K Sato M Apr 2007 Induction of metallothionein synthesis by cilostazol in mice and in human cultured neuronal cell lines Biological amp Pharmaceutical Bulletin 30 4 791 4 doi 10 1248 bpb 30 791 PMID 17409522 Qiu XS Tang NL Yeung HY Lee KM Hung VW Ng BK Ma SL Kwok RH Qin L Qiu Y Cheng JC Jul 2007 Melatonin receptor 1B MTNR1B gene polymorphism is associated with the occurrence of adolescent idiopathic scoliosis Spine 32 16 1748 53 doi 10 1097 BRS 0b013e3180b9f0ff PMID 17632395 S2CID 6777367 External links edit Melatonin Receptors MT2 IUPHAR Database of Receptors and Ion Channels International Union of Basic and Clinical Pharmacology Archived from the original on 2016 03 03 Retrieved 2008 12 05 This article incorporates text from the United States National Library of Medicine which is in the public domain Retrieved from https en wikipedia org w index php title Melatonin receptor 1B amp oldid 1212937237, wikipedia, wiki, book, 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