Progesterone induces dephosphorylation and inactivation of tyrosine hydroxylase in rat hypothalamic dopaminergic neurons.
After in vivo treatment, progesterone initially decreases tyrosine hydroxylase (TH) activity in the TIDA neurons, but subsequently increases TH activity with prolonged treatment. In order to explore the cellular mechanism for progesterone's effect, this study examined the acute inhibitory action of progesterone on TH activity in rat fetal hypothalamic dopaminergic neurons in vitro. Progesterone caused a rapid decrease in TH activity within 1 h, which was sustained for at least 6 h. However, the dopaminergic cells became refractory to progesterone with continuous treatment for 12 h to 10 days. Progesterone (10-100 nM) treatment suppressed TH activity in a concentration-dependent manner. The inhibitory effect of progesterone was dependent on prior exposure to estradiol. Whereas progesterone decreased TH activity, A ring-reduced metabolites of progesterone did not alter TH activity, suggesting that the response was specific to progesterone. Progesterone decreased radiolabeled phosphate incorporation into TH protein. Okadaic acid, a phosphoprotein phosphatase inhibitor, prevented the progesterone-induced suppression of TH activity and phosphate incorporation into TH, implicating dephosphorylation of TH as the cellular mechanism. In contrast, neither TH mRNA levels nor TH protein content was altered after 1 or 12 h of progesterone treatment. Progesterone decreased TH activity after pretreatment of the hypothalamic cells for 2 or 24 h with actinomycin D, an RNA synthesis inhibitor, suggesting that increased transcription does not mediate the effect. These data indicate that the acute progesterone-induced decline in TH activity is caused by dephosphorylation of TH.
Arbogast
Lydia A
LA
Department of Physiology, Southern Illinois University School of Medicine, Carbondale 62901-6512, USA. larbogast@som.siu.edu
Voogt
James L
JL
D000818:Animals; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000378:metabolism*; D009994:Osmolar Concentration; D010766:Phosphorylation / Q000187:drug effects; D011374:Progesterone / Q000494:pharmacology*; D011372:Progestins / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*
D011372:Progestins; D012333:RNA, Messenger; D011374:Progesterone; D004958:Estradiol; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine