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

Abstract

The progesterone (P 4 ) rise on proestrous afternoon is associated with dephosphorylation of tyrosine hydroxylase (TH) and reduced TH activity in the stalk-median eminence (SME), which contributes to the proestrous prolactin surge in rats. In the present study, we investigated the time course for P 4 effect on TH activity and phosphorylation state, as well as cAMP levels and protein phosphatase 2A (PP2A) activity and quantity, in the SME on proestrous morning and afternoon. P 4 (7 . 5 mg/kg, s.c.) treatment on proestrous afternoon decreased TH activity and TH phosphorylation state at Ser-31 and Ser-40 within 1 h, whereas morning administration of P 4 had no 1 h effect on TH. PP2A activity in the SME was enhanced after P 4 treatment for 1 h on proestrous afternoon without a change in PP2A catalytic subunit quantity, whereas P 4 treatment had no effect on PP2A activity or quantity on proestrous morning. cAMP levels in the SME were unchanged with 1 h P 4 treatment. At 5 h after P 4 treatment, TH activity and phosphorylation state declined coincident with an increase in plasma prolactin in both P 4 -treated morning and afternoon groups. PP2A activity in the SME was unchanged in 5 h P 4 -treated rat. Our data suggest that P 4 action on tuberoinfundibular dopaminergic (TIDA) neurons involves at least two components. A more rapid (1 h) P 4 effect engaged only on proestrous afternoon likely involves the activation of PP2A. The longer P 4 action on TIDA neurons is evident on both the morning and afternoon of proestrus and may involve a common, as yet unidentified, mechanism.

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].…”

Differential and Interactive Effects of Ligand-Bound Progesterone Receptor A and B Isoforms on Tyrosine Hydroxylase Promoter Activity.

“…Although sparsely explored, a stimulatory effect for progesterone during late pregnancy is suggested by the ability of RU486 treatment to decrease TH protein levels in the medial basal hypothalamus (55). In contrast to its stimulatory action, progesterone can also have an inhibitory effect on the tuberoinfundibular dopaminergic neurons with a decrease in TH activity, TH phosphorylation levels and TH mRNA levels in tuberoinfundibular dopamine neurons observed on the evening of prooestrus, but RU486 treatment on pro-oestrus had no effect on the progesterone induced suppression of TH mRNA levels (6,(8)(9)(10). Combined these studies indicate progesterone has multiple effects on TH in vivo.…”

“…These data suggest a stimulatory action on TH gene expression through the classical nuclear PR. The inhibitory effect of progesterone is observed on the afternoon of pro-oestrus, with the initial response of decreased TH phosphorylation state in the median eminence followed by decreased TH mRNA levels in the arcuate nucleus (8)(9)(10). The stimulatory effect of progesterone on TH content is not limited to the hypothalamic neurons, as progesterone increases TH content in the olfactory bulb (11).…”

Hypothalamic Control of Prolactin Secretion, and the Multiple Reproductive Functions of Prolactin

“…181 In contrast, the predominant direct action of estradiol on NEDA neurons is one of inhibition, 171,178,179,182 suppressing TH expression 183,184 and activity 185 and reducing secretion of dopamine into the portal blood, 186 thereby facilitating prolactin secretion. 168 The acute inhibitory actions appear to involve a rapid decrease in the phosphorylation of TH, inactivating the enzyme and reducing dopamine synthesis, 189,192 and hence do not seem to involve the classical steroid hormone action via gene transcription. 170 The effects of progesterone on NEDA activity are equally complex.…”