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Function of the luteinizing hormone/chorionic gonadotropin receptor (2022)
Prema Narayan
Introduction
The luteinizing hormone/chorionic gonadotropin receptor (LHCGR) belongs to the G protein-coupled receptor superfamily and together with the follicle-stimulating receptor (FSHR) and thyroid stimulating hormone receptor (TSHR) comprises the family of glycoprotein hormone receptors. LHCGR is the target for luteinizing hormone (LH) secreted by the pituitary as well as the highly homologous chorionic gonadotropin (CG) secreted by the placenta of primates and equids. LHCGR is predominantly expressed in the gonads and is critical for male sex differentiation in the fetus and for adult reproductive function in males and females.
*LHCGR gene and protein structure
Physiological functions of LH via the LHCGR
The pivotal physiological role of LHCGR can be attributed to its predominant expression and action in the gonads as underscored by the reproductive phenotypes in individuals harboring inactivating and activating mutations in the receptor [3]. In the testes, LHCGR is expressed only in the interstitial Leydig cells. During male fetal development, LHCGR in the fetal Leydig cells is activated by hCG expressed by the placenta to produce the testosterone required for male sexual differentiation [17]. Postnatally, LHCGR is activated by LH to produce testosterone required for pubertal development, male secondary sexual characteristics, and spermatogenesis [18, 19]. In the ovary, LHCGR regulates several functions and its expression undergoes dynamic changes during the ovarian cycle. LHCGR is expressed in the theca cells at all stages of follicle development and activation by LH stimulates the synthesis of androgens which are converted to estrogens by aromatase expressed in the granulosa cells and thereby regulates puberty and development of female secondary sexual characteristics [20, 21]. In the preovulatory follicle, LHCGR is also expressed in the mural granulosa cells and its activation by the mid-cycle LH surge terminates preovulatory follicle growth and triggers paracrine and autocrine pathways resulting in ovulation [21, 22]. Following ovulation, LH activation of LHCGR in the luteinized granulosa cells stimulates progesterone production to transiently maintain the corpus luteum [23]. However, upon fertilization, hCG produced by the placenta binds LHCGR to maintain ovarian luteal function and produce progesterone required to maintain the endometrium in the secretory state for the first few weeks of pregnancy (detailed more in Chapter 20).
Signaling pathways
LHCGR activates several signaling pathways in the testes and ovaries. LHCGR was one of the first GPCRs shown to activate more than one G protein, namely Gαs and Gαq/11 [24, 25]. The Gαs-dependent signaling pathway is physiologically relevant in both testes and ovaries. LHCGR activates Gαq/11-dependent signaling under high LH concentrations and at high receptor densities, such as during the time of ovulation, and is physiologically important only in the ovaries. LHCGR also activates the ERK1/2 and the PI3/AKT signaling pathways. The functional importance and the details of these pathways have been elucidated by studies predominantly in cells transfected with LHCGR and in animal models.
Signal transduction in the testes
The canonical pathway that facilitates the trophic effects of LH and hCG and regulates steroidogenesis in the Leydig of the testes is the cAMP pathway [3, 5]. Upon ligand binding and receptor activation, LHCGR couples with Gαs thereby activating adenylyl cyclase, increasing the intracellular levels of cAMP, and subsequent activation of protein kinase A (PKA). PKA phosphorylates and activates steroid acute regulatory protein (StAR), thereby facilitating its translocation into the mitochondria [26]. PKA also activates transcription factors, notably the cAMP regulatory element-binding protein (CREB) and the co-regulatory CREB binding protein, CBP. Consequently, the expression of StAR and several steroidogenic enzymes is upregulated for the production of testosterone in Leydig cells [27].
Recent studies indicate that, in Leydig cells, activation of the cAMP/PKA pathway by LHCGR causes transactivation of the epidermal growth factor receptor (EGFR) resulting in ERK1/2 signaling and steroid production [28-31]. cAMP-induced EGFR transactivation appears to be important for rapid but not long-term steroidogenesis as pharmacological inhibition of the ERK1/2 pathway inhibits acute steroidogenesis [28, 32]. While some studies suggest that ERK1/2 stimulates steroidogenesis by phosphorylating StAR, thereby facilitating its translocation into the mitochondria [28, 32], others suggest that regulation is more complex, involving phosphorylation of transcription factors that regulate the transcription of the StAR gene [33]. Studies in mice lacking MEK1 and 2 demonstrate that ERK1/2 regulates the expression of genes required for testosterone production [34]. Currently, evidence suggests that LHCGR transactivates EGFR by two distinct pathways. The first is an intracellular pathway that involves the cAMP/PKA-dependent activation of Ras and subsequent phosphorylation and activation of ERK1/2 [29, 31]. This pathway is important for steroidogenesis. The second is the transactivation of EGFR that occurs through the matrix metalloprotease (MMP) dependent release of soluble EGFR ligands [35]. This pathway, however, does not appear to be important in Leydig cell steroidogenesis [28, 30]. Cell culture and in vivo studies demonstrated that LHCGR-mediated activation of the ERK1/2 cascade also mediates the proliferation of postnatal Leydig cells and inhibits apoptosis of immature Leydig cells [36-38].
*Signal transduction in the ovary
*Differential signaling by LH and hCG
*Receptor di/oligomers
*Receptor internalization and downregulation
*Mutations and polymorphisms in LHCGR
Extragonadal expression of LHCGR
The major physiological roles of LHCGR can be attributed to their expression in the testes and ovaries. The phenotypes of individuals with activating and inactivating mutations in LHCGR and the phenotypes of genetically modified mouse models that mimic constitutive or absent LHCGR action can be explained by the classical action of LHCGR in the gonads [18, 96-101]. However, there is a controversial body of literature suggesting that LHCGR is expressed in several extragonadal tissues, including the reproductive tract, adrenal glands, and blood vessels [102, 103]. Several reports of extragonadal expression are based on the detection of mRNA fragments or proteins with molecular weights that do not match the gonadal LHCGR [102]. LHCGR is expressed in the primate and human endometrium, but its expression appears to be dynamic. The receptor is expressed in the luminal and glandular epithelial cells of the endometrium during the secretory but not proliferative phase and in the stromal cells surrounding the spiral arteries during the first 25 days of pregnancy [104]. It is proposed that the temporal LHCGR signaling activates genes required for implantation. A mature form of LHCGR protein capable of hormone binding has been reported in the rat fetal and adult nervous tissue [105, 106]; however, their functional role remains to be determined. Adrenal expression of functional LHCGR has been reported in a woman with pregnancy-associated Cushing’s syndrome and again after menopause [107, 108]. Studies in animal models have determined that ectopic expression of LHCGR is a consequence of elevated gonadotropin levels [109].
Concluding remarks
The importance of LHCGR in sexual development and adult reproductive function is well established. In the last couple of decades, great progress has been made in understanding the structural determinants of ligand-receptor interactions and receptor activation, the complex network of signaling pathways mediated by LHCGR, and differential regulation by LH and hCG. Further elucidating the molecular details and the cross-talk between the different signaling cascades and functional significance of receptor complexes that regulate testicular and ovarian function may provide new therapeutic approaches for reproductive disorders.
