The delta opioid receptor influences circadian rhythms in human N/TERT-1 keratinocytes through the β-arrestin pathway
Junnarkar, Seetanshu Bharat
Date of Issue2019-07-31
School of Biological Sciences
Institute of Medical Biology
The circadian rhythmicity of critical skin cell functions related to homeostasis, regeneration and aging has recently been highlighted. In this study, we suggest an important link between cutaneous opioid receptor (OPr) activity and circadian rhythmicity. We find that activation of the Delta-opioid receptor (DOPr) by its endogenous agonist Met-enkephalin in N/TERT-1 keratinocytes results in a phase shift in the expression of the core clock gene Per2 and in the nuclear localization of the DOPr - β-arrestin 1 complex. Furthermore, DOPr activation enhances and induces a phase shift in the rhythmic binding of β-arrestin1 to the Per2 promoter. Coupled with this finding, β-arrestin1 was found to regulate the transcription of its target genes, including Per2, by facilitating histone 4 acetylation. Taken together, we propose that activation of DOPr leads to a phase shift in Per2 expression via β-arrestin1 facilitated chromatin remodelling. We believe our results have potential implications in wound healing, DNA repair and chronopharmacology.