Dopamine-2 receptor activation suppresses PACAP expression in gonadotrophs.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is expressed at a high level in the fetal pituitary and decreases profoundly between embryonic day 19 and postnatal day 1 (PN1), with a further decrease from PN1 to PN4. In this series of experiments, we investigated the hypothesis that dopamine 2 receptor (Drd2) activation interrupts a cAMP-dependent feed-forward loop that maintains PACAP expression at a high level in the fetal pituitary. Using single-cell RT-PCR of pituitary cell cultures from newborn rats, Drd2 mRNA was identified in gonadotrophs that were also positive for PACAP mRNA. PACAP expression in pituitary cultures from embryonic day 19 rats was suppressed by the PACAP6-38 antagonist and by the Drd2 agonist bromocriptine. Increasing concentrations of bromocriptine inhibited cAMP production as well as cAMP signaling based on cAMP response element-luciferase activity, decreased PACAP promoter activity, and decreased PACAP mRNA levels in αT3-1 gonadotroph cells. Furthermore, blockade of dopamine receptors by injecting haloperidol into newborn rat pups partially reversed the developmental decline in pituitary PACAP mRNA that occurs between PN1 and PN4. These results provide evidence that dopamine receptor signaling regulates PACAP expression under physiological conditions and lend support to the hypothesis that a rise in hypothalamic dopamine at birth abrogates cAMP signaling in fetal gonadotrophs to interrupt a feed-forward mechanism that maintains PACAP expression at a high level in the fetal pituitary. We propose that this perinatal decline in pituitary PACAP reduces pituitary follistatin which permits GnRH receptors and FSH-β to increase to facilitate activation of the neonatal gonad.
Division of Endocrinology, Metabolism & Diabetes (S.J.W., D.T.G., J.B.H., A.R.W.O., J.M., J.P.M.), and Department of Anatomy and Neurobiology (R.Q.Y., J.P.M.), University of Louisville, Louisville, Kentucky 40202.
Stephen J
SJ
Winters
Dushan T
DT
Ghooray
Rong Q
RQ
Yang
Joshua B
JB
Holmes
Andrew Rw
AR
O'Brien
Jay
J
Morgan
Joseph P
JP
Moore
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D001971:Bromocriptine / Q000494:pharmacology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression; D052681:Gonadotrophs / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D010902:Pituitary Gland / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D065127:Dopamine D2 Receptor Antagonists; D005419:Flavonoids; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D017448:Receptors, Dopamine D2; D001971:Bromocriptine; D000242:Cyclic AMP; D006220:Haloperidol; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one