Regulation of mouse kappa opioid receptor gene expression by retinoids.

The effect of retinoids on the expression of kappa opioid receptor (KOR) gene was examined in normal and transgenic animals. KOR-lacZ transgene expression was specifically elevated in KOR-positive areas of the developing CNS by depleting vitamin A from animal diets. The endogenous KOR mRNA species, including all three isoforms, were also upregulated by depleting vitamin A in developing animals. Change in the expression of isoforms a and b is similar in prenatal stages but differs during postnatal development. Interestingly, upregulation of isoform c is most significant postnatally. The regulation of KOR gene by vitamin A was substantiated in a mouse embryonal carcinoma P19 culture system in which retinoic acid (RA), the most potent ingredient of vitamin A, was able to suppress the expression of all the three KOR isoforms and KOR protein. The RA-mediated suppression was blocked by an RA receptor antagonist and a histone deacetylase (HDAC) inhibitor. By using a reporter transfection assay in P19 cells, the potential genetic element responsible for RA-mediated suppression of KOR gene expression was located to intron 1 of the mouse KOR gene, which could also be blocked by HDAC inhibitor. Furthermore, suppression of KOR gene expression by RA in P19 cells appeared to be an indirect event and required protein synthesis. A role of RA in KOR gene regulation during developmental stages was discussed.