Apoptosis of lactotrophs induced by dopamine is mediated by the short isoform of D2 receptor

D. B. RADL; J. FERRARIS; V. BOTTI; A. SEILICOVICH; D.K.SARKAR; D. PISERA

San Diego

Congreso; 92º Annual Meeting of the Endocrine Society; 2010

Dopamine, by its interaction with D2 receptors in the pituitary gland, is the main regulator of lactotrophs function. We have described that dopamine induces apoptosis of lactotrophs in an estrogen-dependent manner. Also, we have observed in an in vivo model that cabergoline, a D2 receptor agonist, induces apoptosis in anterior pituitary gland of ovariectomized rats only when they were treated with estradiol. D2 receptor has two isoforms, long (D2L) and short (D2S). It has been demonstrated that both isoforms are expressed in lactotrophs. Although they have a similar pharmacological profile, both isoforms can interact with different Gi proteins, and differ in the mechanism that leads to MAPK activation. The aim of this work was to study the role of D2 receptor isoforms in the apoptosis of lactotrophs and the participation of p38 MAPK in the proapoptotic action of dopamine. Lactotroph-derived PR1 cells transfected with an empty expression vector, or with vectors containing cDNA encoding D2L or D2S receptors, were incubated with or without estradiol (10-9 M) for 48 h and with dopamine (10-6 M) for further 4 h. Apoptosis was determined by the quantitation of nucleosomes in an ELISA assay and by the TUNEL method. Dopamine, in the presence of estradiol, induced apoptosis only in cells expressing the D2S receptor. To study the role of p38 MAPK in the apoptotic action of dopamine, the cells were incubated in the presence of an inhibitor of p38 MAPK pathway (SB203850). SB203850 decreased dopamine-induced apoptosis in D2S expressing cells. Additionally, western blot analysis of the phosphorylated form of p38 MAPK indicates the activation of this MAPK by dopamine.These data suggest that, in the presence of estradiol, dopamine induces apoptosis of lactotrophs by its interaction with D2S receptors. In addition, the p38 MAPK pathway may be involved in the proapoptotic action of dopamine.