Stress-induced epigenetic regulation of κ-opioid receptor gene involves transcription factor c-Myc

Abstract

Exposure to stress is associated with adverse emotional and behavioral responses. Whereas the κ-opioid receptor (KOR) system is known to mediate some of the effects, it is unclear whether and how stress affects epigenetic regulation of this gene. Because the KOR gene can use two promoters (Pr1 and Pr2) and two polyadenylation signals (PA1 and PA2), it is also interesting whether and how these distinct regulatory mechanisms are differentially modulated by stress. The current study examined the effects of stress on these different regulatory mechanisms of the KOR gene. Results showed that stress selectively increased the expression of KOR mRNA isoforms controlled by Pr1 and terminated at PA1 in specific brain areas including the medial-prefrontal cortex, hippocampus, brainstem, and sensorimotor cortex, but not in the amygdala or hypothalamus. These effects correlated with altered epigenetic state of KOR Pr1 chromatin, as well as elevation and increased recruitment of the principal transcription factor c-Myc, which could activate Pr1. Stress-induced modulation of Pr1 was further validated using glutamate-sensitive murine hippocampal cell line, HT22. The results revealed a common molecular mechanism underlying the effect of stress on selected chromatin regions of this gene at the cellular level and in the context of whole animal and identified a critical role for c-Myc in stress-triggered epigenetic regulation of the KOR gene locus. This study sheds light on the mechanisms of stress-induced epigenetic regulation that targets specific chromatin segments and suggests certain KOR transcripts and its principal transcription factor c-Myc as potential targets for brain-area-specific intervention.

β-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia

“…43 KOR activation in DA neurons has been reported to inhibit the activity of the DA system, which has a critical role in the regulation of the brain reward system. 44 However, how KOR functions in glial cells is still poorly understood.…”

The role of the dynorphin/κ opioid receptor system in anxiety

“…Similar to acute stress, repeated exposure to stress also results in dynorphin release and subsequent κ opioid receptor activation [92] . Following repeated swim stress, κ opioid receptor mRNA expression was regulated in a region-specific manner in the brain [93] . In recent reports, exposure to repeated stress resulted in the dysregulation of κ receptor signaling in the DRN through a p38 MAPK-dependent mechanism [92] .…”

Chronic nicotine-induced changes in gene expression of delta and kappa-opioid receptors and their endogenous ligands in the mesocorticolimbic system of the rat

“…Additionally, qPCR analysis of PDYN and KOR mRNAs also included the LHA. Studies report that varying densities of these mRNAs are present in the selected brain regions (Flaisher‐Grinberg et al, ; Harlan et al, ; Lin et al, ; Mansour et al, ).…”

“…Dynorphin peptides derived from PDYN are the main endogenous ligands for κ‐opioid receptors (KORs) (Noble et al, ). Varying levels of KOR mRNA are present in the mesocorticolimbic system (Flaisher‐Grinberg, Persaud, Loh, & Wei, ; Mansour et al, ). KORs are expressed on VTA dopamine neurons (Chefer, Backman, Gigante, & Shippenberg, ), while in the striatum, they are located on the soma/dendrites of iSPNs (Banghart et al, ; Scherrer et al, ; Svingos et al, ) and on axon terminals with cholinergic, GABAergic and dopaminergic characteristics (Svingos et al, ).…”