The role of G-protein- and β-arrestin dependent signaling mechanisms in the tonic regulation of prolactin secretion
Márk Oláh1, Zsuzsanna Szepesi2, Ibolya Bodnár1, György M. Nagy1 & Zsolt Tidrenczel1
It is well known that hypophyseotrophic dopamine (DA) exhibits a tonic inhibitory effect on pituitary lactotrops in vivo. We have previously observed that prolactin (PRL) cells obtained from lactating rats become partially resistant to DA following a brief suckling period compared to non-suckled control female rats. This, so-called desensitization (and a parallel appearance of tolerance) to DA is mediated through by a selective change of protein phosphatase 2A (PP2A) in the pituitary lactotrops. Besides the known Gi-protein-cAMP-PKA pathway, stimulation of D2-receptor (D2-R) leads to the activation of the p44/42 extracellular-regulated kinase (ERK1/2) in the pituitary gland. Moreover, an additional signal-transduction pathway has recently been described in case of the striatal D2-R that is a G-protein independent and β-arrestin dependent mechanism. In this signaling β-arrestin is coupled with PP2A that dephosphorilates, therefore inactivates protein kinase B (Akt). We have investigated the changes in phosphorilation of ERK1/2 and Akt following physiological (suckling) and/or pharmacological (inhibitor of DA biosynthesis and/or D2-R antagonist) manipulations of the hypophyseotrophic DA system using western-blot technique. Suckling stimulus compared to 4 h separation of lactating rats resulted in higher phosphorilation level of ERK1/2 in the AL as well as in male rats treated with DA biosynthesis inhibitor α-methyl-p-thyrosine (αMPT, 250 mg/kg b.w. ip.). Phospho-ERK1/2 content of the NIL was also higher after αMPT treatment in male rats. Suckling had no effect on Akt phosphorilation, but systematic administration of D2-R blocker, haloperidol (2.5 mg/kg b.w. ip.) as well as αMPT significantly increased the level of phospho-Akt (Thr308) in both the AL and the NIL in male rats. These observations may help to explain the differences in the regulatory mechanism between male and female rats as well as the development of DA tolerance and dependence on the tonic regulation of lactotrops in lactating animals.
This work was supported by the National Scientific Research Fund (OTKA T-04337) and the Ministry of Health (ETT 177/2006) to GMN.