Estrogen inhibits D2S receptor-regulated Gi3 and Gs protein interactions to stimulate prolactin production and cell proliferation in lactotropic cells

Abstract

The neurotransmitter dopamine (DA) is known to inhibit prolactin (PRL) secretion and the proliferation of lactotropes in the pituitary gland. Dopamine-2 (D2) receptor short (D2S) isoform is expressed in a reduced level while the D2 receptor long (D2L) isoform is expressed in an elevated level during estradiol (E(2))-induced PRL production and cell proliferation in lactotropes. To evaluate the role of these D2 receptor isoforms in E(2)-regulated lactotropic cell function, we compared E(2) effects on the level of PRL, cell proliferation, and G proteins in enriched lactotropes and lactotrope-derived PR1 cells containing only D2S isoform (D2S cells), D2L isoform (D2L cells), or no D2 receptor (V cells). Additionally, we determined the effects of G protein blockade on the E(2)-induced PRL production and cell proliferation in these cells. We here show that E(2) actions on G proteins, PRL production, and cell proliferation were maximally achieved in D2S cells, oppositely or marginally achieved in D2L cells, and absent in V cells. We also show that the DA and pertussis toxin modulations of E(2) actions on PRL, G proteins, and cell proliferation were maximally achieved in D2S cells compared with in D2L or V cells. Furthermore, we provide evidence for the existence of an inhibitory action of Gi3 on Gs that is under the control of the D2S receptor and is inhibited by E(2). These results suggest that the suppression of D2S-regulated Gi3 inhibition of Gs protein may be one of the mechanisms controlling E(2)-activated PRL synthesis and cell proliferation in lactotropes.