Regulation of mouse kappa opioid receptor gene expression by retinoids

The effect of retinoids on the expression of kappa opioid receptor (KOR) ge ne was examined in normal and transgenic animals. KOR-lacZ transgene expres sion 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 simi lar in prenatal stages but differs during postnatal development. Interestin gly, upregulation of isoform c is most significant postnatally. The regulat ion of KOR gene by vitamin A was substantiated in a mouse embryonal carcino ma P19 culture system in which retinoic acid (RA), the most potent ingredie nt of vitamin A, was able to suppress the expression of all the three KOR i soforms and KOR protein. The RA-mediated suppression was blocked by an RA r eceptor antagonist and a histone deacetylase (HDAC) inhibitor. By using a r eporter transfection assay in P19 cells, the potential genetic element resp onsible for RA-mediated suppression of KOR gene expression was located to i ntron 1 of the mouse KOR gene, which could also be blocked by HDAC inhibito r. Furthermore, suppression of KOR gene expression by RA in P19 cells appea red to be an indirect event and required protein synthesis. A role of RA in KOR gene regulation during developmental stages was discussed.