Progesterone Induces Dephosphorylation and Inactivation of Tyrosine Hydroxylase in Rat Hypothalamic Dopaminergic Neurons

Abstract

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.

Progesterone decreases tyrosine hydroxylase phosphorylation state and increases protein phosphatase 2A activity in the stalk-median eminence on proestrous afternoon

“…A similar decrease in radiolabeled phosphate incorporation into TH protein within 1h was observed in hypothalamic cells in vitro (Arbogast & Voogt 2002), although the specific serine sites were not identified in this earlier study. The concerted dephosphorylation of regulatory serines supports the notion of a common phosphatase mechanism.…”

“…Thus, the 22% increase in total PP2A activity may actually reflect a more marked increase in P 4 responsive cells or terminals in the SME. A role for a phosphatase being involved in P 4 action is further supported by the fact that okadaic acid, a PP2A and PP1 inhibitor, reversed the P 4 -dependent decrease in radiolabeled phosphate incorporation into TH protein in hypothalamic cells in vitro (Arbogast & Voogt 2002). P 4 did not alter PP2Ac protein level in the SME at 1h after P 4 administration, suggesting activation of existing PP2Ac enzyme rather than production of new PP2Ac enzyme protein.…”

“…P 4 regulation of TH activity and prolactin secretion requires previous or concomitant treatment with estradiol (Arbogast & Ben-Jonathan 1990; Arbogast & Voogt 2002; Beattie et al 1972; Gonzalez et al 1980, Morrell et al 1989) and estradiol stimulates P 4 receptor expression (Kraus et al 1994; Scott et al 2002; Shughrue et al 1997). Classical nuclear P 4 receptors are found in dopaminergic neurons of hypothalamus in rats (Fox et al 1990; Lonstein & Blaustein 2004; Sar 1988).…”

Lack of Plasma Norepinephrine Cyclicity, Increased Estradiol during the Follicular Phase, and of Progesterone and Gonadotrophins at Ovulation in Women with Premenstrual Syndrome

“…P, precursor of the neurosteroid allopregnanolone, might work by enhancing GABA-ergic tone during these phases of the cycle [11]. However, it might suppress serotonin and catecholamine levels by other mechanisms, thus leading to depression [29,30].…”

Effect of Progesterone Withdrawal on Hypothalamic Mechanisms Related to Prolactin Release in Late Pregnant Rats

“…TH regulation is exerted mainly by two mechanisms, a rapid one involving changes in the phosphorylation status of the pre-existent enzyme and a long-term mechanism involving changes in the synthesis or degradation of the protein [2]. Acute P 4 treatment induces inactivation of the enzyme through dephosphorylation [37,38] and suppresses TH mRNA [22]. However, long-term P 4 treatment stimulates DA release into the portal vessels [21], enhances DA turnover in arcuate nucleus and median eminence [20] and increases TH activity in the arcuate nucleus [22].…”