PACAP induces FSHβ gene expression via EPAC

Area of Science:

• Reproductive Endocrinology
• Molecular Signaling
• Hormone Regulation

Background:

• Gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), are crucial for reproductive function and regulated by gonadotropin-releasing hormone (GnRH).
• Pituitary adenylate cyclase activating peptide (PACAP) is a hormone that modulates gonadotropin expression, acting through distinct signaling pathways compared to GnRH.
• PACAP primarily activates Gαs and cAMP signaling, while GnRH activates Gαq and calcium signaling in gonadotropes.

Purpose of the Study:

• To compare the signaling pathways by which PACAP and GnRH induce the expression of the FSH beta subunit (FSHβ).
• To elucidate the molecular mechanisms underlying PACAP-mediated FSHβ induction.

Main Methods:

• Primary mouse pituitary cells were treated with GnRH or PACAP for 4 and 24 hours.
• Analysis of FSHβ expression and secretion.
• Investigation of signaling pathways involving G proteins (Gαs, Gαq), cAMP, EPAC, small G proteins (Ras, Rac, CDC42), MAPK, and cFOS.

Main Results:

• Both GnRH and PACAP induced FSHβ expression and FSH secretion in a time-dependent manner.
• PACAP-induced FSHβ expression requires the cAMP sensor EPAC and involves the MAPK pathway, specifically p38 MAPK.
• PACAP utilizes Ras, Rac, and CDC42 small G proteins to activate p38 MAPK, leading to cFOS induction and subsequent FSHβ expression.

Conclusions:

• PACAP induces FSHβ expression through a cAMP-dependent pathway involving EPAC, small G proteins, p38 MAPK, and cFOS.
• This pathway differs from GnRH signaling and highlights a novel mechanism for regulating FSHβ production.
• Understanding these distinct signaling cascades provides insights into the complex regulation of gonadotropin synthesis and secretion.