Stanford University School of Medicine, USA.
Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, CA, 92521, USA.
Mol Cell Endocrinol. 2019 Jul 15;492:110438. doi: 10.1016/j.mce.2019.04.018. Epub 2019 Apr 26.
Gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), are heterodimers of a common α subunit and unique β subunits. Regulation of their levels, primarily by GnRH, is critical for reproductive function. Several other hormones modulate gonadotropin expression, either independently or by modifying the responsiveness to GnRH. Pituitary adenylate cyclase activating peptide (PACAP) is one such hormone. Four-hour treatment of female mouse primary pituitary cells by either GnRH or PACAP induced FSHβ expression, while 24-h treatment repressed FSHβ. Both PACAP and GnRH caused FSH secretion into the medium. In the gonadotropes, PACAP activates primarily Gαs and increases concentration of cAMP, while GnRH primarily functions via Gαq and increases calcium concentration. Herein, we compared PACAP and GnRH signaling pathways that lead to the induction of FSHβ expression. Interestingly, constitutively active Gαs represses LHβ and induces FSHβ expression, while Gαq induces both β-subunits. We determined that FSHβ induction by PACAP requires functional EPAC, a cAMP sensor protein that serves as a guanine exchange factors for small G proteins that then bridges cAMP signaling to MAPK pathway. We further demonstrate that in addition to the prototypical small G protein Ras, two members of the Rho subfamily, Rac and CDC42 are also necessary for PACAP induction of FSHβ, likely via activation of p38 MAPK that leads to induction of cFOS, a critical transcription factor that is necessary and sufficient for FSHβ induction. Therefore, PACAP-induced cAMP pathway leads to MAPK activation that stimulates cFOS induction, to induce the expression of FSHβ subunit and increase FSH concentration.
促性腺激素，黄体生成素（LH）和卵泡刺激素（FSH），是由一个共同的α亚基和独特的β亚基组成的异二聚体。它们的水平调节主要受 GnRH 调控，对生殖功能至关重要。其他几种激素通过调节 GnRH 的反应性或独立地调节促性腺激素的表达。垂体腺苷酸环化酶激活肽（PACAP）就是这样一种激素。用 GnRH 或 PACAP 对雌性小鼠原代垂体细胞进行 4 小时处理，可诱导 FSHβ表达，而 24 小时处理则抑制 FSHβ表达。PACAP 和 GnRH 均可引起 FSH 分泌到培养基中。在促性腺激素细胞中，PACAP 主要激活 Gαs，增加 cAMP 浓度，而 GnRH 主要通过 Gαq 起作用并增加钙浓度。在此，我们比较了导致 FSHβ表达诱导的 PACAP 和 GnRH 信号通路。有趣的是，组成性激活的 Gαs 抑制 LHβ并诱导 FSHβ表达，而 Gαq 诱导两个β亚基。我们确定 PACAP 诱导 FSHβ表达需要功能性 EPAC，这是一种 cAMP 传感器蛋白，作为小 G 蛋白的鸟嘌呤核苷酸交换因子，然后将 cAMP 信号传递到 MAPK 途径。我们进一步证明，除了典型的小 G 蛋白 Ras 外，Rho 亚家族的两个成员 Rac 和 CDC42 也是 PACAP 诱导 FSHβ所必需的，可能通过激活 p38 MAPK 来诱导 cFOS 的诱导，cFOS 是一种关键的转录因子，对于 FSHβ的诱导是必需且充分的。因此，PACAP 诱导的 cAMP 途径导致 MAPK 激活，刺激 cFOS 诱导，从而诱导 FSHβ亚基的表达并增加 FSH 浓度。
