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 D-2 dopamine receptors and an autocrine loop mediated by nerve growth factor (NGF) and one group (nonresponder) lacks both D-2 receptors and NGF production. D-2 receptor expression in these cell lines is dependent on NGF. Indeed, NGF inactivation in responder cells decreases D-2 receptor density, while NGF treatment induces D-2 receptor expression in nonresponders. Here we show that inactivation of p75(NGFR), but not of trkA, resulted in D-2 receptor loss in responder cells and prevented D-2 receptor expression induced by NGF in the nonresponder. Analysis of nuclear factor-kappaB (NF-kappaB) nuclear accumulation and binding to corresponding DNA consensus sequences indicated that in NGF-secreting responder cells, but not in nonresponders, NF-kappaB is constitutively activated. Moreover, NGF treatment of nonresponder cells induced both nuclear translocation and DNA binding activity of NF-kappaB complexes containing p50, p65/RelA, and cRel subunits, an effect prevented by anti-p75(NGFR) antibodies. Disruption of NF-kappaB nuclear translocation by SN50 remarkably impaired D-2 receptor expression in responder cells and prevented D-2 gene expression induced by NGF in nonresponders. These data indicate that in prolactinoma cells the effect of NGF on D-2 receptor expression is mediated by p75(NGFR) in a trkA-independent way and that NGF stimulation of p75(NGFR) activates NF-kappaB, which is required for D-2 gene expression. We thus suggest that NF-kappaB is a key transcriptional regulator of the D-2 gene and that this mechanism may not be confined to pituitary tumors, but could also extend to other dopaminergic systems.