Nerve growth factor regulates dopamine D2 receptor expression in prolactinoma cell lines via p75NGFR-mediated activation of nuclear factor-κB

Two groups of prolactinoma cell lines were identified. One group (responder) expresses both D₂ dopamine receptors and an autocrine loop mediated by nerve growth factor (NGF) and one group (nonresponder) lacks both D₂ receptors and NGF production. D₂ receptor expression in these cell lines is dependent on NGF. Indeed, NGF inactivation in responder cells decreases D₂ receptor density, while NGF treatment induces D₂ receptor expression in nonresponders. Here we show that inactivation of p75_NGFR, but not of trkA, resulted in D₂ receptor loss in responder cells and prevented D₂ receptor expression induced by NGF in the nonresponder. Analysis of nuclear factor-κB (NF-κB) nuclear accumulation and binding to corresponding DNA consensus sequences indicated that in NGF-secreting responder cells, but not in nonresponders, NF-κB is constitutively activated. Moreover, NGF treatment of nonresponder cells induced both nuclear translocation and DNA binding activity of NF-κB complexes containing p50, p65/RelA, and cRel subunits, an effect prevented by anti-p75_NGFR antibodies. Disruption of NF-κB nuclear translocation by SN50 remarkably impaired D₂ receptor expression in responder cells and prevented D₂ gene expression induced by NGF in nonresponders. These data indicate that in prolactinoma cells the effect of NGF on D₂ receptor expression is mediated by p75_NGFR in a trkA-independent way and that NGF stimulation of p75_NGFR activates NF-κB, which is required for D₂ gene expression. We thus suggest that NF-κB is a key transcriptional regulator of the D₂ gene and that this mechanism may not be confined to pituitary tumors, but could also extend to other dopaminergic systems.