The expression, regulation and signal transduction pathways of the mammalian gonadotropin-releasing hormone receptor.
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.
Cheng
K W
KW
Department of Obstetrics and Gynaecology, The University of British Columbia, Vancouver, Canada.
Leung
P C
PC
D000818:Animals; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D008322:Mammals; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010053:Ovary / Q000378:metabolism; D010902:Pituitary Gland / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011966:Receptors, LHRH / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D014158:Transcription, Genetic
D011966:Receptors, LHRH; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins