Epigenetic regulation of melatonin receptors in neuropsychiatric disorders

Abstract

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. LINKED ARTICLES: This article is part of a themed section on Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.16/issuetoc.

Figure 1

Regulation of chromatin conformation by histone acetylation and methylation. Histone acetylation, methylation or other covalent modifications of lysine residues on the N‐terminal tail of the histone core can alter gene transcription via changes in the accessibility of DNA to regulatory factors.

Figure 2

Proposed mechanism for the induction of MT₁ receptors by VPA. VPA activates the transcription of MT₁ receptors by causing chromatin remodelling, mediated by HDAC inhibition and MT₁ promoter hyperacetylation. VPA also acts via intracellular kinases to regulate the expression of transcription factors that control the activity of the MT₁ promoter, suggesting a role for this drug in the transcriptional kinetics of MT₁ receptor expression.

Figure 3

An overview of the potential therapeutic benefits of epigenetic up‐regulation of melatonin receptors. While VPA is shown in this illustration, a similar epigentic up‐regulation of melatonin receptors can be induced by other HDAC inhibitors.