Role of nuclear receptor NR4A2 in prolactin secretion by female rat lactotrophs

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The NR4A nuclear receptor family (NR4A1, NR4A2, and NR4A3) comprises stimulus-responsive orphan nuclear receptors expressed in endocrine tissues, including the anterior pituitary gland. However, their functional roles in lactotrophs remain poorly understood. Because prolactin (PRL) secretion varies markedly across reproductive states, it provides a useful physiological model for investigating gene expression changes associated with distinct secretory conditions. In this study, we examined the expression patterns of the three Nr4a genes in the rat pituitary under physiological and pharmacological conditions associated with altered PRL secretion and evaluated the contribution of each NR4A family member to PRL secretion. Pituitary Nr4a gene expression increased in parallel with elevated PRL secretion during pregnancy and lactation. In contrast, Nr4a expression declined after weaning as PRL secretion decreased, and the nocturnal increase in Nr4a expression observed during early pseudopregnancy was absent after mid-pregnancy. Pseudopregnancy was also associated with an overnight increase in PRL secretion accompanied by increased pituitary Nr4a expression. These coordinated changes in PRL secretion and Nr4a expression were suppressed by dopaminergic inhibition in vivo and in primary pituitary cultures, whereas oxytocin transiently enhanced PRL secretion and Nr4a expression. Importantly, knockdown of Nr4a2, but not Nr4a1 or Nr4a3, significantly reduced PRL secretion without affecting Prl mRNA expression. These findings demonstrated that NR4A family members were associated with physiological PRL secretory states and identified NR4A2 as a selective regulator of PRL secretion at the level of hormone release rather than transcription.