Regulation and Function of Melatonin Receptors

*包括人类在内的哺乳动物的松果腺会产生一种名为褪黑激素的化学信使或激素，白天的水平非常低，夜间血液循环中的水平最高。这种激素通过与大脑中的生物钟相互作用，在调节昼夜节律方面发挥着重要作用。它还参与调节许多其他生理活动，包括神经内分泌功能、免疫反应和生殖。此外，褪黑素是一种细胞保护激素，可以保护细胞免受自由基和环境神经毒素的伤害。为了产生不同的效果，褪黑素在血液中流动，到达大脑或其他器官，在那里它与位于其目标细胞上的特定位置或受体结合。褪黑素结合传递的信号导致一系列细胞反应，从而改变其靶细胞和器官的功能。重要的是，老年人的血液中这种保护性激素的水平显著下降，这被认为与年龄相关的渐进性生理功能障碍的发病有关。*我们由NSERC资助的研究表明，某些通过表观遗传机制改变基因活性的药物，会导致大脑和培养细胞中褪黑素受体数量的显著上调或增加。表观遗传学涉及基因表达的调节，而不改变潜在的DNA序列。这项研究计划旨在确定上述药物诱导的褪黑素受体增加如何影响年轻或衰老大脑中褪黑素的信号和功能。褪黑素已被证明可以增加大脑某一区域新细胞的形成，该区域对记忆和学习等认知功能至关重要。然而，褪黑素及其受体的进行性丧失会导致衰老哺乳动物的褪黑激素能系统的活性降低。鉴于认知和褪黑素能活动都随着年龄的增长而下降，预计我们增加褪黑素受体数量的新策略加上这种激素的管理，将维持或恢复老化大脑中的认知和其他基本功能。此外，这项建议旨在阐明这一新颖和独创的策略涉及的机制，以上调大脑和其他靶组织中的褪黑素受体。阐明这些机制和褪黑激素受体上调的功能相关性将是褪黑素生理学的重大进展，并为理解其在哺乳动物生物学中的不同作用奠定基础。最终，应该有可能利用这一知识来保护褪黑素受体的表达和功能，从而保持这种荷尔蒙的体内平衡益处。

***The pineal gland in mammals including humans, produces a chemical messenger or hormone called melatonin, which exhibits very low daytime levels, with peak levels present in the circulation at night. This hormone plays an important role in the regulation of circadian rhythms by interacting with the biological clock in the brain. It is involved in modulating numerous other physiological activities including neuroendocrine function, immune responses and reproduction. Moreover, melatonin is a cytoprotective hormone that protects cells against the injurious effects of free radicals and environmental neurotoxins. In order to produce its diverse effects, melatonin travels in the bloodstream to reach the brain or other organs, where it binds to specific sites or receptors, which are located on its target cells. Melatonin binding conveys a signal which results in a cascade of cellular responses, with consequent changes in the function of its target cells and organs. Importantly, older individuals exhibit a significant decrease in their blood levels of this protective hormone, which is thought to be related to the progressive age-related onset of physiological dysfunction.****Our NSERC-funded studies have shown that certain drugs, which alter gene activity by an epigenetic mechanism, cause a significant upregulation or increase in the number of melatonin receptors in the brain and in cultured cells. Epigenetics involves the regulation of gene expression, without changes to the underlying DNA sequence. This research program is aimed at determining how the above mentioned drug-induced increases in melatonin receptors influences the signaling and function of melatonin in the young or aging brain. Melatonin has been shown to increase the formation of new cells in an area of the brain which is essential for cognitive function such as memory and learning. However, the progressive loss of both melatonin and its receptors results in a decrease in activity of the melatonergic system in aging mammals. Given the decline in both cognition and melatonergic activity with aging, it is anticipated that our novel strategy for increasing the number of melatonin receptors coupled with administration of this hormone, will maintain or restore cognition and other essential functions in the aging brain. In addition, this proposal is aimed at clarifying the mechanisms involved in this novel and original strategy for upregulating melatonin receptors in the brain and other target tissues. Clarification of these mechanisms and the functional correlates of melatonin receptor upregulation will be a significant advance in melatonin physiology and provide a base for understanding its diverse roles in mammalian biology. Ultimately, it should be possible to utilize this knowledge in order to preserve melatonin receptor expression and function, thus maintaining the homeostatic benefits of this hormone.******