Regulation and Function of Melatonin Receptors

包括人类在内的哺乳动物的松果体会产生一种叫做褪黑素的化学信使或激素，这种激素在白天的含量很低，在夜间的循环中会达到峰值。这种激素通过与大脑中的生物钟相互作用，在调节昼夜节律中起着重要作用。它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，褪黑素在血液中到达大脑或其他器官，在那里它与位于目标细胞上的特定部位或受体结合。褪黑素结合传递一个信号，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生理功能障碍的进行性发作有关。

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.