Nuclear melatonin receptors
Abstract
Melatonin is a hormone produced in the central nervous system (pineal gland) and peripheral tissues (appendix, pancreas, adrenal glands, thymus, prostate, ovaries, placenta). It is secreted by blood cells (platelets, lymphocytes and eosinophils) and endothelium. Melatonin is found in mast cells, endometrium, cerebellum, neuroendocrine cells of the airways, paraganglia, inner ear, liver, gallbladder, cortical layer of the kidneys. The key role of melatonin is determined by the fact that endogenous rhythms of the body are subordinated to the rhythms of its production. The number of melatonin publications is constantly increasing, indicating the versatility of its effects resulting from its active participation in many physiological and pathological processes. There is convincing evidence that melatonin participates in almost all vital processes that control many body functions, including sleep and activities of the immune, endocrine, and cardiovascular systems. This is manifested by the universal therapeutic properties of melatonin, which, in turn, are determined by its peculiar biological role. Since melatonin easily traverses biological membranes, it can exert its effect in almost all cells. Some of its effects are receptor-mediated, others are receptor-independent. The main effects of melatonin are associated with its effect on the membrane receptors, MT1 and MT2, that belong to the family of receptors associated with G-proteins. These receptors are responsible for chronobiological effects and regulation of circadian rhythms. MT1 and MT2 are present in peripheral organs and cells, and they contribute, for example, to some extent to immunological reactions and vasomotor control. MT1 is more responsible for vasoconstriction, while MT2 causes vasodilation. The nuclear melatonin receptors, ROR-α/RZR-β, have been discovered relatively recently. Apparently, many immune-stimulating and antitumor effects of melatonin are mediated through them. The antioxidant function of melatonin is partially based on receptor interaction, but some antioxidant properties do not require participation of the receptor apparatus. This review examines and discusses the information available in the Russian and international literature on the potential role of orphan nuclear retinoid receptors of the ROR/RZR subfamily in regulating the activity of the pineal hormone melatonin. The mechanisms of receptor-DNA interaction and known coactivators, tissue-specific features of the expression of various isoforms of the receptor, and its regulation are described. The array of probable targets for regulation by receptors is analyzed, the most common of which are the lymphoid and central nervous systems. The review identifies some prospects for further study of melatonin receptors.
Downloads
References
1. Vasendin D.V. Biomedical effects of melatonin: some results and prospects of studying. Bulletin of the Russian Military medical Academy. 2016; 55 (3):171–178.
2. Michurina S.V., Vasendin D.V., Ishchenko I.Yu. Physiological and biological effects of melatonin: some results and prospects of study. I.M. Sechenov Russian Journal of Physiology. 2018. 104(3):257–271.
3. Reiter RJ, Tan DX, Rosales-Corral S, et al. Mitochondria: Central organelles for melatonin’s antioxidant and anti-aging actions. Molecules. 2018. 23(2):509. doi: 10.3390/molecules23020509
4. He C. , Ma T., Shi J. et al. Melatonin and its receptor MT1 are involved in the downstream reaction to luteinizing hormone and participate in the regulation of luteinization in different species. J. Pineal Res. 2016. 61(3):279-90. doi: 10.1111/jpi.12345
5. Do Amaral F.G., Andrade-Silva J., Wilson M.T. et al. New insights into the function of melatonin and its role in metabolic disturbances. Expert Review of Endocrinology and Metabolism. 2019. 14(4):293–300. doi: 10.1080/17446651.2019.1631158
6. Cardinali D.P. Melatonin: Clinical Perspectives in Neurodegeneration. Front. Endocrinol. 2019;10:480. doi: 10.3389/fendo.2019.00480
7. Michurina S.V., Letyagin A.Yu., Shurlygina A.V. et al. Hepato-immune-epiphysis axis of inter system interactions. Melatonin and structural-functional changes in the liver and immune system during obesity and diabetes mellitus type 2. Novosibirsk: «Manuscript Press»; 2019.
8. Lin P.H., Tung Y.T., Chen H.Y. et al. Melatonin Activates Cell Death Programs for the Suppression of Uterine Leiomyoma Cell Proliferation. J. Pineal Res. 2020; 68:e12620
9. Zhao D., Yu Y., Shen Y. et al. Melatonin Synthesis and Function: Evolutionary History in Animals and Plants. Front. Endocrinol. 2019; 10:249. doi: 10.3389/fendo.2019.00249
10. Bocheva G., Slominski R.M., Janjetovic Z. et al. Protective Role of Melatonin and Its Metabolites in Skin Aging. Int. J. Mol. Sci. 2022;23(3):1238. doi: 10.3390/ijms23031238
11. Morvaridzadeh M., Sadeghi E., Agah S Effect of melatonin supplementation on oxidative stress parameters: A systematic review and meta-analysis. Pharmacological Research. 2020; 161:105210. doi: 10.1016/j.phrs.2020.105210
12. Smirnov A.N. Nuclear melatonin receptors. Biochemistry. 2001;66(1): 28–36.
13. Ma H., Kang J., Fan W. et al. ROR: Nuclear Receptor for Melatonin or Not? Molecules. 2021; 26:2693. doi: https:// doi.org/10.3390/molecules26092693
14. Evans R.M., Mangelsdorf D.J. Nuclear Receptors, RXR, and the Big Bang. Cell. 2014;157: 255–266. doi: https://doi.org/10.1016/j.cell.2014.03.012
15. Ladurner A., Schwarz P.F., Dirsch V.M. Natural products as modulators of retinoic acid receptor-related orphan receptors (RORs). Nat. Prod. Rep. 2021; 38: 757. doi: https://doi.org/10.1039/D0NP00047G
16. Liu L., Labani N., Cecon E. et al. Melatonin Target Proteins: Too Many or Not Enough? Front. Endocrinol. 2019; 10:791. doi: https://doi.org/10.3389/fendo.2019.00791.
17. Zhao Y., Xu L., Ding S. et al. Novel protective role of the circadian nuclear receptor retinoic acid-related orphan receptor-α in diabetic cardiomyopathy. J. Pineal Res. 2017; 62. doi: https://doi.org/10.1111/jpi.12378
18. Han D., Wang Y., Chen J. et al. Activation of melatonin receptor 2 but not melatonin receptor 1 mediates melatonin-conferred cardioprotection against myocardial ischemia/reperfusion injury. J. Pineal Res. 2019; 67:e12571. doi: https://doi.org/10.1111/jpi.12571
19. Huang H., Liu X., Chen D. et al. Melatonin prevents endothelial dysfunction in SLE by activating the nuclear receptor retinoic acid-related orphan receptor-α. Int. Immunopharmacol. 2020; 83:106365. doi: https://doi.org/10.1016/j.intimp.2020.106365
20. Clark E.A., Rutlin M., Capano L. et al. Cortical ROR is required for layer 4 transcriptional identity and barrel integrity. eLife. 2020; 9:e52370. doi: https://doi.org/10.7554/eLife.52370
21. Zang M., Zhao Y., Gao L. et al. The circadian nuclear receptor ROR negatively regulates cerebral ischemia–reperfusion injury and mediates the neuroprotective effects of melatonin. BBA Mol. Basis Dis. 2020; 1866:165890. doi: https://doi.org/10.1016/j.bbadis.2020.165890
22. Li Z., Zhao J., Liu H. et al. Melatonin inhibits apoptosis in mouse Leydig cells via the retinoic acid-related orphan nuclear receptor α/p53 pathway. Life Sci. 2020; 246:117431. doi: https://doi.org/10.1016/j.lfs.2020.117431
23. Min H.Y., Son H.E., Jang W.G. Estradiol-induced ROR expression positively regulates osteoblast differentiation. Steroids. 2019;149:108412. doi: https://doi.org/10.1016/j.steroids.2019.05.004
24. Yasui H., Matsuzaki Y., Konno A. et al. Global Knockdown of Retinoid-related Orphan Receptor in Mature Purkinje Cells Reveals Aberrant Cerebellar Phenotypes of Spinocerebellar Ataxia. Neuroscience. 2020; Е. 462:328–336. doi: https://doi.org/10.1016/j.neuroscience.2020.04.004
25. Aquino-Martinez R., Farr J.N., Weivoda M.M. et al. miR-219a-5p Regulates Rorβ During Osteoblast Differentiation and in Age-related Bone Loss. J. Bone Miner. Res. 2019;34:135–144. doi: https://doi.org/10.1002/jbmr.3586
26. Xu L., Zhang L., Wang Z. et al. Melatonin Suppresses Estrogen Deficiency-Induced Osteoporosis and Promotes Osteoblastogenesis by Inactivating the NLRP3 Inflammasome. Calcif. Tissue Int. 2018;103:400–410. doi: https://doi.org/10.1007/s00223-018-0428-y
27. Michurina S.V., Ishchenko I.Yu., Archipov S.A. et al. Аpoptosis in the liver of male DB/DB mice during the development of obesity and type 2 diabetes. Vavilov Journal of Genetics and Breeding. 2020;24(4):435 – 440. doi: 10.18699/VJ20.43-o
28. Kallen J., Izaac A., Be C. et al. Structural States of RORt: X-ray Elucidation of Molecular Mechanisms and Binding Interactions for Natural and Synthetic Compounds. ChemMedChem. 2017;12:1014–1021. doi: https://doi.org/10.1002/cmdc.201700278
29. Kang J., Chen H., Zhang F. et al. RORα Regulates Odontoblastic Differentiation and Mediates the Pro-Odontogenic Effect of Melatonin on Dental Papilla Cells. Molecules. 2021;26:1098. doi: https://doi.org/10.3390/molecules26041098
30. Farez M.F., Calandri I.L., Correale J. et al. Anti-inflammatory effects of melatonin in multiple sclerosis. Bioessays. 2016;38:1016–1026. doi: https://doi.org/10.1002/bies.201600018
31. Gooley J.J. Circadian regulation of lipid metabolism. Proc. Nutr. Soc. 2016; 75:440–450. doi: https://doi.org/10.1017/S0029665116000288
32. Ferlazzo N., Andolina G., Cannata A. et al. Is Melatonin the Cornucopia of the 21st Century? Antioxidants. 2020;9:1088. doi: https://doi.org/10.3390/antiox9111088
33. Xu L., Su Y., Zhao Y. et al. Melatonin differentially regulates pathological and physiological cardiac hypertrophy: Crucial role of circadian nuclear receptor ROR signaling. J. Pineal Res. 2019;67:e12579. doi: https://doi.org/10.1111/jpi.12579
34. Slominski A.T, Kim T.K., Takeda Y. et al. RORα and ROR are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxyand 20,23-dihydroxyvitamin D. FASEB J. 2014; 28: 2775–2789. doi: https://doi.org/10.1096/fj.13-242040
35. Becker-André M., Wiesenberg I., Schaeren-Wiemers N. et al. Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily. J. Biol. Chem. 1994; 269:28531–28534.
36. Hajam Y.A., Rai S. Melatonin and insulin modulates the cellular biochemistry, histoarchitecture and receptor expression during hepatic injury in diabetic rats. Life Sci. 2019; 239:117046. doi: 10.1016/j.lfs.2019.117046
37. Morvaridzadeh M., Sadeghi E., Agah S. Effect of melatonin supplementation on oxidative stress parameters: A systematic review and meta-analysis. Pharmacological Research. 2020; 161:105210. DOI: 10.1016/j.phrs.2020.105210
38. Somalo-Barranco G, Serra C, Lyons D. et al. Design and Validation of the First Family of Photo-Activatable Ligands for Melatonin Receptors. J. Med. Chem. 2022; 65:11229−11240. doi: https://doi.org/10.1021/acs.jmedchem.2c00717
39. Liu J., Clough S.J., Hutchinson A.J. et al. MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective. Pharm. Toxicol. 2016; 56:361–383.
40. Nikolaev G., Robeva R., Konakchieva R. Membrane Melatonin Receptors Activated Cell Signaling in Physiology and Disease Int. J. Mol. Sci. 2022;23(1):471. doi: 10.3390/ijms23010471
