Melanocortin-4 Receptors (MC4R)
Abstract
Melanocortin 4 Receptors (MC4R) merupakan turunan senyawa G protein coupled-receptors (GPCRs). MC4R berperan dalam homeostasis energi, fungsi kardiovaskular, dan sistem reproduksi. Gen MC4R ini menyandi sekitar 332 asam amino dan terkespresi pada hipotalamus. MC4R salah satu protein transmembran dengan memiliki tujuh subtipe protein. Melanocortin-pathway berhubungan dengan pro-opiomelanocortin (POMC) dalam aktivasi leptin sehingga meningkatkan dan menurunkan nafsu makan. Mutasi yang ditemukan pada MC4R berbanding lurus dengan kejadian obesitas. Mutasi yang terjadi bisa karena munculnya defek pada struktur MC4R, ekspresi pada permukaan membran sel, ikatan dengan ligan dan jalur sinyal. POMC akan mengaktivasi atau inaktivasi MC4R sesuai dengan kebutuhan energi tubuh. MC4R akan berikatan dengan agonis α-MSH atau β-MSH dan antagonis AgRP. Kesimpulannya, pengaturan MC4R dalam tubuh meliputi fungsi kardiovaskular, aktivitas insulin dan sistem reproduksi. Sehingga saat ini menjadi target sebagai terapi antiobesitas.
Keywords
Full Text:
PDFReferences
WHO. Prevalance of obesity and Overweight. 2015.
Tao, Y.X. Chapter 6 Mutations in Melanocortin-4 Receptor and Human Obesity. 1st edn. Progress in Molecular Biology and Translational Science. 1st edn. Elsevier Inc. 2019. Available at: https://doi.org/10.1016/S1877-1173(09)88006-X.
Bessesen, D.H. Update on obesity. J Clin Endocrinol Metab. 2008. 93:2027–34.
Data Riskesdas. Prevalensi Obesitas Di Indonesia. 2018.
Bray, M.S. et al. NIH working group report - Using genomic information to guide weight management: From universal to precision treatment. Obesity. 2016. 24(1):14–22. Available at: https://doi.org/10.1002/oby.21381.
Fairbrother, U. et al. Genetics of Severe Obesity. Current Diabetes Reports. 2018. 18(10). Available at: https://doi.org/10.1007/s11892-018-1053-x.
Fatima, M.T. et al. Melanocortin-4 receptor complexity in energy homeostasis, obesity and drug development strategies. Diabetes, Obesity and Metabolism. 2022. 24(4):583–598. Available at: https://doi.org/10.1111/dom.14618.
Hauser, A.S., Attwood, M.M., Rask-Andersen, M., Schioth, H.B., and Gloriam, D.E. Trends in GPCR drug discovery: new agents, targets and indications. Nat. Rev. Drug Discov. 2017. 16, 829–842.
Kühnen, P., Krude, H. and Biebermann, H. Melanocortin-4 Receptor Signalling: Importance for Weight Regulation and Obesity Treatment. Trends in Molecular Medicine. 2019. 25(2):136–148. Available at: https://doi.org/10.1016/j.molmed.2018.12.002.
Gantz I, MiwaH, K.Y., Shimoto, Y., Tashiro, T., Watson, S.J., DelValle, J., et al. Molecular cloning, expres- sion, and gene localization of a fourth melanocortin receptor. J Biol Chem. 1993. 268:15174.
Tao, Y.X. The melanocortin-4 receptor: Physiology, pharmacology, and pathophysiology. Endocrine Reviews. 2010. 31(4):506–543. Available at: https://doi.org/10.1210/er.2009-0037.
Heyder, N. et al. Signal Transduction and Pathogenic Modifications at the Melanocortin-4 Receptor: A Structural Perspective. Frontiers in Endocrinology. 2019. 10(July):1–18. Available at: https://doi.org/10.3389/fendo.2019.00515.
Ringholm, A., Klovins, J., Fredriksson, R., Poliakova, N., Larson, E.T., Kukkonen, J.P., Larhammar, D., and Schiioth, H.B. Presence of melanocortin (MC4) receptor in spiny dogfish suggests an ancient vertebrate origin of central melanocortin system. Eur J Biochem. 2003. 270:213–221.
Rashighi, M. and Harris, J.E. Myocardium Extract from Suckling Rat. HHS Public Access: Physiology & behavior. 2017. 176(3):139–148. Available at: https://doi.org/10.1053/j.gastro.2016.08.014.CagY.
Yang, L. K., and Tao, Y. X. Biased Signaling at Neural Melanocortin Receptors in Regulation of Energy Homeostasis. Biochim Biophys Acta. 2017. 1863(10):2486-2495. Available at:https:// doi:10.1016/j.bbadis.2017.04.010.
Nijenhuis, W.A.J., Oosterom, J. and Adan, R.A.H. AgRP(83–132) Acts as an Inverse Agonist on the Human-Melanocortin-4 Receptor. Molecular Endocrinology. 2001. 15(1):164–171. Available at: https://doi.org/10.1210/mend.15.1.0578.
Ringholm, A., Klovins, J., Fredriksson, R., Poliakova, N., Larson, E.T., Kukkonen, J.P., Larhammar, D., and Schiioth, H.B. Presence of melanocortin (MC4) receptor in spiny dogfish suggests an ancient vertebrate origin of central melanocortin system. Eur J Biochem. 2003. 270:213–221.
Tarnow, P. et al. Mutationally induced disulfide bond formation within the third extracellular loop causes melanocortin 4 receptor inactivation in patients with obesity. Journal of Biological Chemistry. 2003. 278(49):48666–48673. Available at: https://doi.org/10.1074/jbc.M309941200.
Ollmann, M.M., Wilson, B.D., Yang, Y.K., Kerns, J.A., Chen, Y., et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti‐related protein. Science. 1997. 278:135–8.
Watanobe, H., Schiöth, H.B., Wikberg, J.E., Suda, T. The melanocortin 4 receptor mediates leptin stimulation of luteinizing hormone and prolactin surges in steroid-primed ovariectomized rats. Biochem Biophys Res Commun. 1999. 257:860–864.
Heymsfield, S.B. and Wadden, T.A. Mechanisms, Pathophysiology, and Management of Obesity. New England Journal of Medicine. 2017. 376(3):254–266. Available at: https://doi.org/10.1056/nejmra1514009.
DOI: https://doi.org/10.29103/averrous.v9i1.10935
Article Metrics
Abstract Views : 526 times
PDF Downloaded : 9 times
Refbacks
- There are currently no refbacks.
Copyright (c) 2023 Liza Arieska Saiful
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
| Print ISSN | : |
2477-5231 |
| Online ISSN |
: |
2502-8715 |
Publisher:
Fakultas Kedokteran Universitas Malikussaleh
Kampus Fakultas Kedokteran Universitas Malikussaleh, Jl. Meunasah, Uteunkot Cunda, Lhokseumawe, 24351, Provinsi Aceh, Tel/fax : 081376575984, Email: averrous@unimal.ac.id
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.