The ERK Signaling Cascade Inhibits Gonadotropin-stimulated Steroidogenesis

Abstract

The response of granulosa cells to luteinizing hormone (LH) and follicle-stimulating hormone (FSH) is mediated mainly by cAMP/protein kinase A (PKA) signaling. Notably, the activity of the extracellular signal-regulated kinase (ERK) signaling cascade is elevated in response to these stimuli as well. We studied the involvement of the ERK cascade in LH-and FSH-induced steroidogenesis in two granulosa-derived cell lines, rLHR-4 and rFSHR-17, respectively. We found that stimulation of these cells with the appropriate gonadotropin induced ERK activation as well as progesterone production downstream of PKA. Inhibition of ERK activity enhanced gonadotropin-stimulated progesterone production, which was correlated with increased expression of the steroidogenic acute regulatory protein (StAR), a key regulator of progesterone synthesis. Therefore, it is likely that gonadotropin-stimulated progesterone formation is regulated by a pathway that includes PKA and StAR, and this process is down-regulated by ERK, due to attenuation of StAR expression. Our results suggest that activation of PKA signaling by gonadotropins not only induces steroidogenesis but also activates down-regulation machinery involving the ERK cascade. The activation of ERK by gonadotropins as well as by other agents may be a key mechanism for the modulation of gonadotropin-induced steroidogenesis.Gonadotropic hormones, follicle-stimulating hormone (FSH) 1 and luteinizing hormone (LH), which are released from the pituitary, play a crucial role in controlling reproductive function in males and females. The pleotropic effects of gonadotropins are manifested in various cells of the reproductive system including LH and FSH in ovarian granulosa cells, LH in theca interna cells, FSH in testicular Sertoli cells, and LH in Leydig cells (1-3). One of the main effects of both LH and FSH on the ovary is the stimulation of the production of estradiol and progesterone, which play important roles in ovarian function and control of the reproductive cycle (reviewed in Ref. 4). The mechanisms involved in the regulation of progesterone production by ovarian granulosa cells have been characterized in detail. Gonadotropins exert their stimulatory activity via interaction with specific seven-transmembrane receptors, the LH receptor and FSH receptor. Upon binding of the gonadotropins, both receptors stimulate the G s protein, which activates the membrane-associated adenylyl cyclase, causing an elevation of intracellular cAMP (5). This cyclic nucleotide serves as a second messenger for the up-regulation of the steroidogenic acute regulatory protein (StAR) and the cytochrome P450 (P450scc) enzyme system (reviewed in Refs. 6 and 7).Activation of alternative signaling pathways by the gonadotropin receptors was described in the last decade, including calcium ion mobilization, activation of the phosphoinositol pathway, and stimulation of chloride ion influx (reviewed in Ref. 8). However, these gonadotropin-induced signaling processes were not previously implicated in the modulation of s...

Janus Kinase 2 and Calcium Are Required for Angiotensin II-dependent Activation of Steroidogenic Acute Regulatory Protein Transcription in H295R Human Adrenocortical Cells

“…In Y1 mouse adrenal cells PD098059 treatment decreased the forskolin-stimulated increase in StAR steady-state mRNA levels by ϳ50% (44). In primary cultures of rat granulosa the MEK-1 inhibitor U1026 inhibited follicle-stimulating hormonestimulated increase in StAR mRNA (48), while in a transformed cell line U1026 potentiated the stimulatory effects of follicle-stimulating hormone on StAR protein levels (47). These studies indicate that communication between MAPK pathway and cAMP signaling is cell type-dependent.…”

Aromatase expression in the ovary: Hormonal and molecular regulation

“…In granulosa cells, ERK1/2 phosphorylation is stimulated by LH [74][75][76]. Remarkably, LH causes a rapid and transient activation of ERK1/2 in granulosa cells expressing low levels of LH receptors; whereas, if high levels of LH receptor are present, a delayed and more sustained activation of ERK1/2 take place [77].…”

Control of oestradiol secretion and of cytochrome P450 aromatase messenger ribonucleic acid accumulation by FSH involves different intracellular pathways in oestrogenic bovine granulosa cells in vitro

“…Inhibition of ERK phosphorylation with PD-98059 enhanced FSH-stimulated progesterone secretion and intracellular steroidogenic acute regulatory (StAR) protein levels in rat granulosa cells (Seger et al 2001), and a different ERK inhibitor stimulated Cyp19 mRNA levels in rat granulosa cells (Moore et al 2001). Therefore, FSH-stimulated ERK activity appears to attenuate steroidogenesis.…”