Division of Kidney Disease and Hypertension, Department of Medicine, Brown University School of Medicine, Providence, RI, USA.
Department of Nephrology, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China.
Cell Mol Life Sci. 2020 Oct;77(19):3831-3840. doi: 10.1007/s00018-020-03511-0. Epub 2020 Apr 4.
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.
黑素皮质激素系统通过其神经-免疫-内分泌活动在维持体内平衡方面发挥着关键作用，并调节着多种生理功能，包括黑色素生成、炎症、免疫调节、肾上腺皮质类固醇生成、血液动力学、利钠作用、能量平衡、性功能和外分泌分泌。所有黑素皮质激素的病理生物学作用都是通过黑素皮质激素受体来传递的。作为最后一个被克隆和鉴定的黑素皮质激素受体，黑素皮质激素受体 5 (MC5R) 在人类中枢神经系统和许多外周器官系统中广泛表达。然而，MC5R 介导的黑素皮质激素信号传递的确切作用在很大程度上仍然不确定。由于近年来开发出高度选择性的肽模拟 MC5R 激动剂和拮抗剂，以及对 MC5R 敲除动物的研究，我们对 MC5R 病理生物学的理解得到了极大的扩展和加强。有证据表明，MC5R 在调节免疫反应和炎症反应方面起着关键作用，对于调节性行为、体温调节和外分泌分泌（如皮脂分泌、泪液分泌和性信息素的释放）也至关重要。因此，最近的转化努力集中在开发基于拮抗 MC5R 的新型皮脂抑制疗法来治疗皮脂溢和寻常痤疮。相反，选择性 MC5R 激动剂在免疫介导的疾病、代谢内分泌疾病和其他疾病状态（如肾小球疾病和干眼症、皮肤和口腔）中显示出有希望的有益效果。因此，MC5R 介导的信号传递对健康至关重要。MC5R 的治疗靶向代表了一种针对多种疾病的有前途和务实的治疗策略。本文阐述了 MC5R 介导的黑素皮质激素系统的生物物理学，讨论了实验性疾病模型中针对 MC5R 治疗的现有数据，并设想了治疗人类疾病的转化潜力。
