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Nerve Growth Factor Regulates Dopamine D₂ Receptor Expression in Prolactinoma Cell Lines via p75^NGFR-Mediated Activation of Nuclear Factor-B

Division of Pharmacology (C.F., N.G., M.F., A.F., P.S., C.M.) and Division of General Pathology and Immunology (L.T., L.S.), Department of Biomedical Sciences and Biotechnology, University of Brescia, 25123 Brescia, Italy

Address all correspondence and requests for reprints to: C. Missale, Division of Pharmacology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Via Valsabbina 19, 25123 Brescia, Italy.

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-B (NF-B) nuclear accumulation and binding to corresponding DNA consensus sequences indicated that in NGF-secreting responder cells, but not in nonresponders, NF-B is constitutively activated. Moreover, NGF treatment of nonresponder cells induced both nuclear translocation and DNA binding activity of NF-B complexes containing p50, p65/RelA, and cRel subunits, an effect prevented by anti-p75^NGFR antibodies. Disruption of NF-B 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-B, which is required for D₂ gene expression. We thus suggest that NF-B 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.

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