Epigenetic regulation of melatonin receptors in neuropsychiatric disorders
Epigenetic regulation of melatonin receptors in neuropsychiatric disorders
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DOI：
10.1111/bph.14058
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发表时间：
2018-08-01
影响因子：
7.3
通讯作者：
Niles, Lennard P.
中科院分区：
文献类型：
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作者：
Bahna, Sarra G.;Niles, Lennard P.
褪黑激素是哺乳动物松果体的主要吲哚胺激素，具有多种神经调节、神经保护和其他特性。褪黑激素能信号由其两个GPCR（MT 1和MT 2）介导，这两个GPCR在哺乳动物中枢神经系统中广泛表达。褪黑激素水平和受体表达在正常衰老过程中经常显示出下降，并且这种下降在某些疾病状态下可能会加速。褪黑激素能信号的耗竭与神经精神功能障碍和认知、记忆、神经发生和神经恢复过程中的损伤有关。抗惊厥药和情绪稳定剂丙戊酸（VPA）上调培养细胞和大鼠大脑中褪黑激素MT 1和/或MT 2受体的表达。已知VPA通过多种机制影响基因表达，包括调节细胞内激酶途径和转录因子，以及抑制组蛋白脱乙酰酶（HDAC）活性。有趣的是，其他HDAC抑制剂，如在结构上与VPA不同的阿司他丁A，也可以上调褪黑激素受体表达，这与缺乏HDAC抑制活性的VPA类似物丙戊酰胺不同。此外，VPA增加大鼠C6细胞中组蛋白H3乙酰化沿着MT 1基因启动子的长度。这些发现表明，与组蛋白超乙酰化/染色质重塑和基因转录相关变化相关的表观遗传机制参与VPA对褪黑激素受体的上调。在这些受体由于衰老、损伤或疾病而丢失的区域中，MT 1和/或MT 2受体表达的表观遗传诱导可能是用于管理CNS功能障碍和其他病症的有希望的治疗途径。
Melatonin, the primary indoleamine hormone of the mammalian pineal gland, is known to have a plethora of neuroregulatory, neuroprotective and other properties. Melatonergic signalling is mediated by its two GPCRs, MT1 and MT2, which are widely expressed in the mammalian CNS. Melatonin levels and receptor expression often show a decrease during normal ageing, and this reduction may be accelerated in some disease states. Depleted melatonergic signalling has been associated with neuropsychiatric dysfunction and impairments in cognition, memory, neurogenesis and neurorestorative processes. The anticonvulsant and mood stabilizer, valproic acid (VPA), up-regulates melatonin MT1 and/or MT2 receptor expression in cultured cells and in the rat brain. VPA is known to affect gene expression through several mechanisms, including the modulation of intracellular kinase pathways and transcription factors, as well as the inhibition of histone deacetylase (HDAC) activity. Interestingly, other HDAC inhibitors, such as trichostatin A, which are structurally distinct from VPA, can also up-regulate melatonin receptor expression, unlike a VPA analogue, valpromide, which lacks HDAC inhibitory activity. Moreover, VPA increases histone H3 acetylation along the length of the MT1 gene promoter in rat C6 cells. These findings indicate that an epigenetic mechanism, linked to histone hyperacetylation/chromatin remodelling and associated changes in gene transcription, is involved in the up-regulation of melatonin receptors by VPA. Epigenetic induction of MT1 and/or MT2 receptor expression, in areas where these receptors are lost because of ageing, injury or disease, may be a promising therapeutic avenue for the management of CNS dysfunction and other disorders.