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Protein Phosphatase 2A Plays a Role in the Suckling-Induced Changes in the Responsiveness of Pituitary Mammotropes¹

Department of Medical Chemistry, University Medical School of Debrecen (A.M., P.G.), Debrecen; and EGIS Pharmaceuticals Ltd. (M.I.K.F.) and the Neuroendocrine Research Laboratory, Department of Human Morphology and Developmental Biology, Semmelweis University Medical School (G.M.N.), Budapest, Hungary H-1094

Address all correspondence and requests for reprints to: Dr. György M. Nagy, Neuroendocrine Research Laboratory, Department of Human Morphology and Developmental Biology, Semmelweis University of Medicine, Budapest, Tüzoltó u.58, Hungary H-1094. E-mail: nagy-gm{at}ana2.sote.hu

It is well established that PRL secretion is under a tonic inhibition exercised by the hypothalamic dopamine (DA). One feature of this regulation is an immediate withdrawal reaction (elevation of PRL release) of mammotropes after disruption of hypothalamic influence. Although plasma PRL rises rapidly, the suckling stimulus does not cause an acute diminution of hypothalamic DA, but, as we have previously demonstrated, it results in an almost immediate (within 10 min) desensitization of mammotropes as indicated by the change in dose response of DA to inhibit PRL release. Our present investigations relate to the phenomenon of this change in responsiveness of PRL cells. This was accomplished by using the reverse hemolytic plaque assay to evaluate the secretory characteristics of individual PRL secretors derived from lactating rats either before or after a 10-min suckling stimulus. To investigate the mechanism of these changes, the binding characteristics of [³H]spiperone on pituitary membranes from nonsuckled and suckled rats have been compared, and the possible involvement of dephosphorylating enzymes was tested by using okadaic acid (OA) in a dose of 2 nM that preferentially and selectively inhibits protein phosphatase-2A (PP2A) activity. We have also determined the activities of PP1 and PP2A in pituitary tissue samples as well as in enzymatically dispersed cells. Mammotropes from nonsuckled rats exhibited a depression of PRL release after both DA and OA treatment and an elevation after withdrawal of DA. This suggests that the secretory response of mammotropes obtained from nonsuckled rats still shows those two responses that are characteristic of the tonic inhibitory regulation. In contrast, superimposition of suckling in vivo or application of OA together with DA pretreatment in cells from nonsuckled rats in vitro resulted in a disappearance of the dissociation-induced elevation of PRL release, indicating an abolishment of the tonic inhibitory action of DA. Evidence is also presented that the PP2A, but not the PP1, activity of the anterior lobe is significantly lower after a 10-min suckling stimulus. Moreover, DA is able to decrease PP2A activity in dispersed pituitary cells obtained from nonsuckled, but not from suckled, animals. In contrast, there were no differences in either the affinity or the number of binding sites between nonsuckled and suckled rats. Taken together, our results suggest that the suckling-induced decrease in PP2A activity plays a role in the uncoupling of D2 receptors on mammotropes from the tonic inhibitory signaling pathway.