Gonadotrophin Receptors

Abstract

The two gonadotrophin receptors (GnRs), luteinizing hormone receptor (LHCGR) and follicle-stimulating receptor (FSHR), belong to the glycoprotein hormone receptor subgroup of type A G protein-coupled receptors (GPCRs). LHCGR binds specifically the two structurally similar gonadotrophins, luteinizing hormone (LH) and human chorionic gonadotrophin (hCG), and FSHR binds follicle-stimulating hormone (FSH). The receptors reside on plasma membrane and transmit the gonadotrophin signal to target cells using the classical Gs/adenylyl cyclase/cyclic AMP/protein kinase A signaling cascade. Other signaling pathways (e.g., inositol phosphate, calcium) are activated at pharmacological hormone concentrations or at high receptor density. LHCGR is expressed in testicular Leydig cells and in ovarian theca, luteinizing granulosa and luteal cells. FSHR is expressed in testicular Sertoli cells and ovarian granulosa cells. LHCGR activation stimulated Leydig cell steroidogenesis, in particular testosterone production, while FSHR maintains Sertoli cell metabolism, thereby indirectly stimulating spermatogenesis. Recent basic research, using GnR, expressing cells in vitro and genetically modified mice in vivo, has elucidated novel aspects of the molecular mechanisms of gonadotrophin receptor function. The crystal structure of GnRs has also been partly resolved. Numerous inactivating and activating GnR mutations that have been discovered in patients have unraveled the molecular basis of hypogonadism and other aberrations of reproductive endocrine functions. The purpose of this chapter is to review the recent trends of GnR research and how it has elucidated the molecular mechanisms of GnR function and the role of GnR in human reproductive physiology and pathophysiology

Glycoprotein G-protein Coupled Receptors in Disease: Luteinizing Hormone Receptors and Follicle Stimulating Hormone Receptors

“…LHRs are critical to reproduction in both mammalian sexes [ 1 ]. The receptors are mainly present in gonadal cells, including testicular Leydig cells in men [ 2 ] and target cells in the follicle and corpus luteum of the ovary in women. In human follicles, LHRs are found in the theca, interstitial, and granulosa cells of the follicle [ 3 ].…”

“…During puberty, LHRs, responding to pituitary LH, is involved in the production and secretion of androgens, which induce the development of the secondary sex characteristics. In the human testis, where LHRs in Leydig cells and FSHRs in Sertoli cells have been identified using immunohistochemistry [ 4 ], LHRs, stimulated by pituitary LH [ 2 , 5 , 6 ], are necessary for sperm maturation. In females, the LHRs are found in theca cells and differentiated granulosa cells in the ovarian follicle and on luteal cells of the corpus luteum [ 1 ].…”

“…In females, the LHRs are found in theca cells and differentiated granulosa cells in the ovarian follicle and on luteal cells of the corpus luteum [ 1 ]. LHRs expressed in follicular granulosa and theca cells are necessary for the development of the follicle, enhanced steroidogenesis, and ovulation [ 2 , 7 ]. Active LHRs on luteal cells in the corpus luteum, a hormone-producing gland formed from the post-ovulatory follicle, bind LH to maintain synthesis and secretion of estrogen and progesterone by steroidogenic cells.…”

“…hLHRs are coded by a single copy gene that consists of 11 exons and 10 introns and are located on chromosome 2 p21 near the gene for FSHRs [ 10 ]. LHRs are synthesized as a single polypeptide chain that can be divided functionally into three domains [ 1 , 2 , 11 ]. The large N-terminus extracellular domain with 340 amino acids is extensively glycosylated and contains several leucine-rich repeats flanked by cysteine-rich regions and a hinge region.…”

“…The intracellular C-terminal region with 70 amino acids, together with intracellular loops, interacts with G proteins when LHRs are activated by hormone and helps initiate downstream signaling [ 1 , 2 ]. This domain has the most divergent functions of the three domains, regulating the trafficking of receptors from the endoplasmic reticulum to the plasma membrane as well as receptor internalization.…”