GNRH Receptor (gonadotropin-releasing hormone receptor or GNRHR), also known as the luteinizing hormone releasing hormone receptor (LHRHR), is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family. It is expressed on the surface of pituitary gonadotrope cells as well as lymphocytes,breast, ovary, and prostate.
Gonadotropin-releasing hormone (GnRH) was structurally characterized over 40 years ago from porcine and ovine hypothalamic tissues. Since its isolation, it has been biochemically characterized in detail and much is known about the function of each of its 10 amino acids. Almost all GnRH sequences are identical with the exception of variant sequences in the salmon, lamprey and chicken.
GnRH orchestrates reproduction by binding to its high affinity receptor (GnRH-receptor) expressed on the cell surface of gonadotropes in the anterior pituitary gland. Once bound to its receptor, the endocrine message sent from the hypothalamus is decoded resulting in the synthesis and release of LH and FSH from the gonadotropes. The gonadotropins (LH and FSH) in turn promote and sustain gonadal function. Normal reproductive cycles are dependent on timely fluctuations in the pattern of gonadotropin secretions, which are due in part to variations in gonadotropic response to GnRH secretion. These “variations” are mediated through regulation of GnRH receptor gene expression and receptor kinetics. Hence, the concentration and affinity of GnRH receptor present at the cell surface are the principle determinants of the physiologic response to GnRH secretion.
Gonadotropin-releasing hormone receptors are synthesized and expressed by gonadotropes located within the anterior pituitary gland. These are basophilic cells that represent a small percentage (8-15%) of the cell types located within the anterior pituitary gland. The other cell types include the somatotropes, mammotropes, thyrotropes, and corticotropes. The gonadotropes are distributed throughout the anterior pituitary gland nestled in a capillary plexus that demarcates the distal end of the portal vasculature. The portal vasculature originates within the median eminence of the hypothalamus and extends down the pituitary stalk to the anterior pituitary gland.
Gonadotropes have a single class of high-affinity binding sites for GnRH on their plasma membranes. Receptors number varies over the estrous cycle in direct response to gonadal steroids and hypothalamic GnRH. Additionally, increases in GnRH receptor number correspond to increases in receptor mRNA, suggesting control at the transcriptional level.
Estradiol increases the number of receptors and this increase is evidenced during the periovulatory period. This increase has been reported for many species, including sheep, mice, and cattle. Estradiol increases both the frequency and amplitude of GnRH pulses during the follicular phase. Conversely, high levels of progesterone during the luteal phase decrease the frequency of GnRH pulses which results in a decreased receptor number. Other gonadal hormones also function to regulate the GnRH receptor. In rats, receptor synthesis is increased by activin A while inhibin decreases receptor number but doesn’t affect synthesis of new receptor.
Commonly, ligands will regulate their own receptor and the GnRH receptor is not different in this respect. Continuous delivery of GnRH to ovariectomized ewes results in a dramatic decrease in receptor number. Delivery in a manner which mimics the physiological pulsatile pattern results in an increase in receptor number. The GnRH receptor is unusual in that it is up- or down-regulated by GnRH depending on the duration and level of GnRH exposure. The increase in receptor number requires both protein and RNA synthesis while down-regulation does not. The effect of a complete absence of GnRH is evidenced in a strain of mice that have a mutation in their gene for GnRH. These mice have absolutely no circulating levels of LH or FSH and, hence, no gonadal function.
Thus, GnRH receptor numbers vary dramatically over the course of the estrous cycle. In the rat, the highest levels are observed between metestrus and early proestrus with levels declining rapidly during the preovulatory LH surge. GnRH receptor mRNA has also been shown to fluctuate throughout the cycle and reach a maximum level on the afternoon of proertrus. This fluctuation in receptor number can be duplicated in cultured gonadotrope cells. Cultures incubated with levels of progesterone comparable to those found midcycle, demonstrate approximately 500 plasma membrane receptors per cell while exposure to estradiol greatly increases receptor number to 15,000 to 20,000 per cell.
McCallum, J. M. (2002). Immunological detection of extra-pituitary gonadotropin-releasing hormone receptors.
Porter, M. B. (2002). The equine GnRH receptor: A study in receptor structure, function, and physiologic behavior.