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Signal Transduction Pathways Involved in
Prolactin Regulation
Prolactin (PRL, luteotropic hormone) is a protein hormone produced in the anterior pituitary that induces lactation and inhibits the release of other gonadotropic hormones. Positive regulators of PRL release include vasoactive intestinal polypeptide (VIP), estrogen, and thyrotropin-releasing hormone (TRH), while negative regulators include dopamine and thyroid hormone. VIP exerts its effects by the G-protein-mediated activation of adenyl cyclase (AC) and its downstream effectors (cAMP and protein kinase A (PKA)) that activate a kinase cascade that culminates in gene expression and the subsequent release of PRL. On the other hand, TRH induces PRL expression through activation of the phospholipase C (PLC) signaling pathway. Activation of PLC cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) to form diacylglycerol (DAG) and D-myo-inositol-1,4,5-trisphosphate (IP3). IP3 regulates intracellular Ca2+ by binding to the IP3 receptor on the endoplasmic reticulum (ER) and stimulating its release from the ER. Free intracellular Ca2+ can bind to calmodulin and this Ca2+-calmodulin complex, in the presence of cAMP, activates PKA by binding to the regulatory subunit of the enzyme. DAG binds to and activates protein kinase C (PKC). Like PKA, PKC also activates kinase cascades culminating in gene expression. Dopamine binds to the D2 dopamine receptor and decreases AC activity. Estrogen directly inhibits the PRL promoter and can overcome the inhibitory effect of dopamine. Thyroid hormone also directly stimulates the PRL promoter.
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References:
Benker, G., et al., Control of prolactin secretion. Klin. Wochenschr., 68, 1157-1167 (1990).
Pernasetti, F., et al., Thyroid hormone inhibits the human prolactin gene promoter by interfering with activating protein-1 and estrogen stimulations. Mol. Endocrinol., 11, 986-996 (1997).
Schaufele, F., Regulation of estrogen receptor activation of the prolactin enhancer/promoter by antagonistic activation function-2-interacting proteins. Mol. Endocrinol., 13, 935-945 (1999).
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