Signal Transduction Pathways Involved in Prolactin Regulation

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Signal Transduction Pathways Involved in
Prolactin Regulation
SIGMA-ALDRICH
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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 thy-rotropin-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).