Regulation of rat Sertoli cell function by FSH: possible role of phosphatidylinositol 3-kinase/protein kinase B pathway

Abstract

The FSH molecular mechanism of action is best recognized for its stimulation of the adenylyl cyclase/cAMP pathway via activation of a G protein. Recently, links between cAMP, phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB) signaling pathways in thyroid and granulosa cells have been observed. The aim of this study was to investigate the possible role of the PI3K/PKB pathway in FSH regulation of Sertoli cell function. Twenty-day-old rat Sertoli cell cultures were used. An increase in phosphorylated PKB (P-PKB) levels in response to FSH and dibutyryl-cAMP was observed. These increments in P-PKB levels were not observed in the presence of two PI3K inhibitors, wortmannin and Ly 294002. Inhibition of protein kinase A (PKA) by H89 did not decrease FSH stimulation of P-PKB levels. Taken together, these results indicate that FSH increases P-PKB levels in a PI3K-dependent and PKA-independent manner in rat Sertoli cells. In addition, wortmannin partially inhibited the ability of FSH to stimulate two well-known parameters of Sertoli cell function -transferrin secretion and lactate production -at doses equal to or lower than 0·1 µM. Related to lactate production, a decrease in FSH stimulation of lactate dehydrogenase activity and of basal and FSH-stimulated glucose uptake was observed in the presence of wortmannin. These metabolic changes were in most cases accompanied by changes in the levels of P-PKB. Altogether, these results suggest a meaningful role of the PI3K/PKB pathway in the mechanism of action of FSH in rat Sertoli cells.

Novel mechanisms of the regulation of Protein kinase B in adipocytes; implications for Protein kinase A, Epac, Phosphodiesterases 3 and 4

“…In other cell types various results have been obtained. In cardiomyocytes [37], isoproterenol-induced phosphorylation of PKB was PKA and PI3K dependent, whereas, in COS cells [19], cAMP-induced PKB activation was PKA-dependent but PI3K-independent, and in Sertoli cells [39], dbcAMP-induced activation of PKB was PKAindependent but PI3K-dependent. These data strengthen the hypothesis about the specificity of certain signalling events with regard to different tissues.…”

A Novel Epac-Rap-PP2A Signaling Module Controls cAMP-dependent Akt Regulation

“…cAMP modulates Akt in different cell types, including fibroblasts (33,34,45,63), hepatocytes (42), adipocytes (41,64), cardiomyocytes (40), skeletal muscle (43), neurons (48), Schwann (39), endothelial (46), and endocrine cells (38,65). Specifically, in thyroid cells, the role of Akt in TSH-mediated proliferation of nontransformed cells is still controversial; either no effects (66) or both positive (67-69) and negative (47) effects of TSH on Akt phosphorylation/activity have been reported.…”

“…cAMP can either stimulate (33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43) or inhibit (44 -50) Akt activity. We have previously reported that cAMP inhibited Akt activity in PCCL3 thyroid cells via the GTP-binding protein Rap1b (47) and suggested that it played a role in TSH mitogenic action in these cells.…”

Sertoli-Germ Cell Anchoring Junction Dynamics in the Testis Are Regulated by an Interplay of Lipid and Protein Kinases

“…Interestingly, there is accumulating evidence that the PI3K/PKB pathway plays an important role in the formation and stabilization of AJs, linking AJ components to the cytoskeleton in keratinocytes, intestinal epithelial cells, mammary epithelial cells, and Caco-2/15 cells (18,19). In the testis, PI-4,5-P 2 and phosphoinositide-specific phospholipase C have been identified in the ES (20), and the PI3K/PKB signaling pathway has recently been shown to be regulated by follicle-stimulating hormone in 20-day-old Sertoli cells (21)(22)(23). However, little is known regarding the upstream and downstream mediators of the PI3K/PKB signaling pathway in the testis and its contribution to junction dynamics, especially at the apical ES.…”