The neuropeptide Y (NPYVpeptide YY (PYY) Yl receptor (Y1R) subtype transduces NPY/PYY regulation of several important responses including feeding, anxiolysis, vasoconstriction, and mitogenesis. Because the level of receptor expression can modulate NPY/PYY responses, we studied transcriptionally active agents for effects on Y1R mRNA levels and binding activity. In serum-starved SK-N-MC neuroblastoma cells, 0.1 (iM 12-O-tetradecanoylphorbol 13-acetate (TPA) causes a rapid, transient increase in Y1R mRNA levels (peak 2.6 fold at 8 hr), but l uM all t tans retinoic acid (RA) causes a rapid, sustained decrease in Y1R mRNA levels, > 2.5-fold decrease maximal by 4 hr for up to 24 hr compared to controls (DMSO-treated). The the RAinduced decrease in Y1R involves two mechanisms: 1} significantly decreased Y1R mRNA stability; Ihe tj/2 of Y1R mRNA from RA-treated cells is 1.5 hr versus 3 hr for controls; 2) decreased transcription rate of the Y1R gene; nuclear runoff assays show a significant decrease in newly transcribed Y1R mRNA in RA-treated cells. The RAinduced effects involve preexisting cellular proteins as a decrease in Y l R mRNA levels is seen in cells pretreated with cycloheximide. Furthermore since concentrations as low as 1 nM RA also strongly inhibit Y1R mRNA accumulation, RAR proteins may be specifically involved. Specific Y1R binding activity was also significantly decreased after treatment with RA. Y1R binding activity in SK-N-MC membranes decreased after 8 hr treatment with RA (583 + 109 vs 687 + 81 fmol/mg protein, mean + SEM) and was significantly lower than control after 24 hr (368 ±25 vs 496 + 28 fmol/mg protein, p < .05). These data show that retinoic acid is a negative regulator of Y1R gene transcription, mRNA stability, and receptor protein expression in SK-N-MC cells. RA may be an important physiologic agent modulating Y1R expression and NPY/PYY activity; RA and TPA may be acting via an AP-1 site recently reported upstream of an alternative splice site utilized by the Y1R gene in SK-N-MC cells (JBC 270:27272,1995).