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Signal Transduction Pathways Involved in Prolactin Regulation
SIGMA-ALDRICH
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
promotor and can overcome the inhibitory effect of dopamine. Thyroid hormone also directly
stimulates the PRL promotor.
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).