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Melanocortin 5 receptor signaling pathway in health and disease

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Abstract

Melanocortin hormone system plays a key role in maintaining the homeostasis of our body via their neuro-immune-endocrine activities and regulates a diverse array of physiological functions, including melanogenesis, inflammation, immunomodulation, adrenocortical steroidogenesis, hemodynamics, natriuresis, energy homeostasis, sexual function, and exocrine secretion. The pathobiologic actions of all melanocortins are conveyed by melanocortin receptors. As the last melanocortin receptor to be cloned and characterized, melanocortin receptor 5 (MC5R) is widely expressed in both central nervous system and a number of peripheral organ systems in man. However, the exact effect of the MC5R mediated melanocortinergic signaling remains largely uncertain. Owing to the recent advances in developing highly selective peptidomimetic agonists and antagonists of MC5R and also to studies in MC5R knockout animals, our understanding of MC5R pathobiology has been greatly expanded and strengthened. Evidence suggests that MC5R plays a key role in governing immune reaction and inflammatory response, and is pivotal for the regulation of sexual behavior, thermoregulation, and exocrine secretion, like sebogenesis, lacrimal secretion and release of sex pheromones. As such, recent translational efforts have focused on developing novel sebum-suppressive therapies for seborrhoea and acne vulgaris based on antagonizing MC5R. Conversely, selective MC5R agonists have demonstrated promising beneficial effects in immune-mediated diseases, metabolic endocrinopathies and other disease conditions, such as glomerular diseases and dry eyes, skin and mouth. Thus, MC5R-mediated signaling is essential for health. Therapeutic targeting of MC5R represents a promising and pragmatic therapeutic strategy for diverse diseases. This review article delineates the biophysiology of MC5R-mediated biophysiology of the melanocortin hormone system, discusses the existing data on MC5R-targeted therapy in experimental disease models, and envisages the translational potential for treating human diseases.

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Acknowledgements

This work was supported in part by the U.S. National Institutes of Health grant DK114006.

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  1. Yahong Xu and Xuejing Guan are co-first authors that contributed equally to this work.

Authors and Affiliations

  1. Division of Kidney Disease and Hypertension, Department of Medicine, Brown University School of Medicine, Providence, RI, USA

    Yahong Xu & Rujun Gong

  2. Department of Nephrology, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China

    Yahong Xu & Rong Zhou

  3. Division of Nephrology, Department of Medicine, The University of Toledo College of Medicine, Toledo, OH, USA

    Xuejing Guan & Rujun Gong

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  1. Yahong Xu
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Correspondence to Rujun Gong.

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Dr. Gong reports research funding from the Mallincrodt Pharmaceuticals, which is not related to this study. Dr. Gong served as a consultant to the Questcor Pharmaceuticals and the Mallincrodt Pharmaceuticals. All the other authors declared no competing interests.

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Xu, Y., Guan, X., Zhou, R. et al. Melanocortin 5 receptor signaling pathway in health and disease. Cell. Mol. Life Sci. 77, 3831–3840 (2020). https://doi.org/10.1007/s00018-020-03511-0

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