Cheng K W, Leung P C
Department of Obstetrics and Gynaecology, The University of British Columbia, Vancouver, Canada.
Can J Physiol Pharmacol. 2000 Dec;78(12):1029-52.
Normal mammalian sexual maturation and reproductive functions require the integration and precise coordination of hormones at the hypothalamic, pituitary, and gonadal levels. Hypothalamic gonadotropin-releasing hormone (GnRH) is a key regulator in this system; after binding to its receptor (GnRHR), it stimulates de novo synthesis and release of gonadotropins in anterior pituitary gonadotropes. Since the isolation of the GnRHR cDNA, the expression of GnRHR mRNA has been detected not only in the pituitary, but also in extrapituitary tissues, including the ovary and placenta. It has been shown that change in GnRHR mRNA is one of the mechanisms for regulating the expression of the GnRHR. To help understand the molecular mechanism(s) involved in transcriptional regulation of the GnRHR gene, the 5' flanking region of the GnRHR gene has recently been isolated. Initial characterization studies have identified several DNA regions in the GnRHR 5' flanking region which are responsible for both basal expression and GnRH-mediated homologous regulation of this gene in pituitary cells. The mammalian GnRHR lacks a C-terminus and possesses a relatively short third intracellular loop; both features are important in desensitization of many others G-protein coupled receptors (GPCRs), Homologous desensitization of GnRHR has been shown to be regulated by various serine-threonine protein kinases including protein kinase A (PKA) and protein kinase C (PKC), as well as by G-protein coupled receptor kinases (GRKs). Furthermore, GnRHR was demonstrated to couple with multiple G proteins (Gq/11, Gs, and Gi), and to activate cascades that involved the PKC, PKA, and mitogen-activator protein kinases. These results suggest the diversity of GnRHR-G protein coupling and signal transduction systems. The identification of second form of GnRH (GnRH-II) in mammals adds to the complexity of the GnRH-GnRHR system. This review summaries our recent progress in understanding the regulation of GnRHR gene expression and the GnRHR signal transduction pathways.
正常哺乳动物的性成熟和生殖功能需要下丘脑、垂体和性腺水平的激素整合及精确协调。下丘脑促性腺激素释放激素（GnRH）是该系统中的关键调节因子；与受体（GnRHR）结合后，它刺激垂体前叶促性腺细胞中促性腺激素的从头合成和释放。自GnRHR cDNA分离以来，不仅在垂体中检测到GnRHR mRNA的表达，还在包括卵巢和胎盘在内的垂体外组织中检测到。已表明GnRHR mRNA的变化是调节GnRHR表达的机制之一。为了帮助理解参与GnRHR基因转录调控的分子机制，最近分离出了GnRHR基因的5'侧翼区域。初步表征研究已在GnRHR 5'侧翼区域鉴定出几个DNA区域，它们负责该基因在垂体细胞中的基础表达和GnRH介导的同源调节。哺乳动物GnRHR缺乏C末端且具有相对较短的第三细胞内环；这两个特征在许多其他G蛋白偶联受体（GPCR）的脱敏中都很重要，GnRHR的同源脱敏已被证明受多种丝氨酸 - 苏氨酸蛋白激酶调节，包括蛋白激酶A（PKA）和蛋白激酶C（PKC），以及G蛋白偶联受体激酶（GRK）。此外，GnRHR被证明与多种G蛋白（Gq/11、Gs和Gi）偶联，并激活涉及PKC、PKA和丝裂原激活蛋白激酶的级联反应。这些结果表明GnRHR - G蛋白偶联和信号转导系统的多样性。哺乳动物中第二种GnRH（GnRH - II）的鉴定增加了GnRH - GnRHR系统的复杂性。本综述总结了我们最近在理解GnRHR基因表达调控和GnRHR信号转导途径方面的进展。
