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J. Biol. Chem., Vol. 277, Issue 39, 35819-35825, September 27, 2002
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From the Department of Laboratory Medicine and Pathobiology,
Banting and Best Diabetes Centre, University of Toronto and the
University Health Network, Toronto, Ontario M5G 1L5
In pituitary lactotrophs the prolactin
gene is stimulated by neuropeptides and estrogen and is
suppressed by dopamine via D2-type receptors. Stimulatory
signals converge on activation of the mitogen-activated protein kinases
ERK1/2, but dopamine regulation of this pathway is not well defined.
Paradoxically, D2 agonists activate ERK1/2 in many cell types. Here we
show that in prolactin-secreting GH4ZR7 cells and primary pituitary
cells, dopamine treatment leads to a rapid, pronounced, and specific decrease in activated ERK1/2. The response is blocked by D2-specific antagonists and pertussis toxin. Interestingly, in stable lines expressing specific pertussis toxin-resistant G
Activation of Go-coupled Dopamine D2 Receptors
Inhibits ERK1/ERK2 in Pituitary Cells
A KEY STEP IN THE TRANSCRIPTIONAL SUPPRESSION OF THE PROLACTIN
GENE*
subunits, toxin treatment blocks dopamine suppression of MAPK in Gi2-
but not Go-expressing cells, demonstrating that
Go-dependent pathways can effect the inhibitory
MAPK response. At the nuclear level, the MEK1 inhibitor U0126 mimics
the D2-agonist bromocryptine in suppressing levels of endogenous
prolactin transcripts. Moreover, a good correlation is seen between the
IC50 values for inhibition of MEK1 and suppression of
prolactin promoter function (PD184352 > U0126 > U0125).
Both dopamine and U0126 enhance the nuclear localization of ERF,
a MAPK-sensitive ETS repressor that inhibits prolactin promoter
activity. In addition, U0126 suppression is transferred by tandem
copies of the Pit-1-binding site, consistent with mapping experiments
for dopamine responsiveness. Our data suggest that ERK1/2 suppression
is an obligatory step in the dopaminergic control of prolactin gene
transcription and that bidirectional control of ERK1/2 function in the
pituitary may provide a key mechanism for endocrine gene control.
*
These studies were supported by a grant from the Canadian
Institutes of Health Research (to H. P. E.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Banting Institute,
Room 110, 100 College St., Toronto, ON M5G 1L5. Tel.: 416-978-8782; Fax: 416-978-4108; E-mail: h.elsholtz@utoronto.ca.
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