Expression and Role of Gonadotropin-Releasing Hormone 2 and Its Receptor in Mammals

Abstract

Gonadotropin-releasing hormone 1 (GnRH1) and its receptor (GnRHR1) drive mammalian reproduction via regulation of the gonadotropins. Yet, a second form of GnRH (GnRH2) and its receptor (GnRHR2) also exist in mammals. GnRH2 has been completely conserved throughout 500 million years of evolution, signifying high selection pressure and a critical biological role. However, the GnRH2 gene is absent (e.g., rat) or inactivated (e.g., cow and sheep) in some species but retained in others (e.g., human, horse, and pig). Likewise, many species (e.g., human, chimpanzee, cow, and sheep) retain the GnRHR2 gene but lack the appropriate coding sequence to produce a full-length protein due to gene coding errors; although production of GnRHR2 in humans remains controversial. Certain mammals lack the GnRHR2 gene (e.g., mouse) or most exons entirely (e.g., rat). In contrast, old world monkeys, musk shrews, and pigs maintain the coding sequence required to produce a functional GnRHR2. Like GnRHR1, GnRHR2 is a 7-transmembrane, G protein-coupled receptor that interacts with Gαq/11 to mediate cell signaling. However, GnRHR2 retains a cytoplasmic tail and is only 40% homologous to GnRHR1. A role for GnRH2 and its receptor in mammals has been elusive, likely because common laboratory models lack both the ligand and receptor. Uniquely, both GnRH2 and GnRHR2 are ubiquitously expressed; transcript levels are abundant in peripheral tissues and scarcely found in regions of the brain associated with gonadotropin secretion, suggesting a divergent role from GnRH1/GnRHR1. Indeed, GnRH2 and its receptor are not physiological modulators of gonadotropin secretion in mammals. Instead, GnRH2 and GnRHR2 coordinate the interaction between nutritional status and sexual behavior in the female brain. Within peripheral tissues, GnRH2 and its receptor are novel regulators of reproductive organs. GnRH2 and GnRHR2 directly stimulate steroidogenesis within the porcine testis. In the female, GnRH2 and its receptor may help mediate placental function, implantation, and ovarian steroidogenesis. Furthermore, both the GnRH2 and GnRHR2 genes are expressed in human reproductive tumors and represent emerging targets for cancer treatment. Thus, GnRH2 and GnRHR2 have diverse functions in mammals which remain largely unexplored.

Comparative Transcriptome Analysis of Gonads for the Identification of Sex-Related Genes in Giant Freshwater Prawns (Macrobrachium Rosenbergii) Using RNA Sequencing

“…Evidence has been accumulated that GnRH2 is required for sexual behavior [41]. Furthermore, initial studies have discovered that GnRHR2 together with its ligand GnRH2, were considered to be novel regulators in driving the reproduction process in mammals [44,45]. Toward this end, our data detected that GnRHR2 was upregulated in ovaries.…”

Reproduction and longevity A Mendelian randomization study of gonadotropin-releasing hormone and ischemic heart disease

“…Second, confounding by population stratification is possible; however both samples mainly concern people of European descent with genomic control, 11 15 and the SNPs were not associated with potential confounders. Third, some SNPs predicting GnRH1 were associated with factors relevant to cardiovascular disease, however GnRH1 is the master of reproduction 7 9 10 suggesting vertical rather than horizontal pleiotropy. Fourth, Mendelian Randomization gives unconfounded estimates, but is open to the selection bias that may occur in observational studies of older adults, 19 because of missing prior deaths from the same underlying cohort.…”

“…Physiologically GnRH1 drives reproduction, 7 9 10 including sex hormones. In randomized controlled trials (conjugated equine) estrogen did not protect against CVD in men or women.…”

“…5 Genetic selection in favour of both fertility and ischemic heart disease (IHD) has been demonstrated. 6 Reproduction is driven centrally by gonadotropin-releasing hormone 1 (GnRH1) 7 likely driven by environmental factors to ensure optimal timing of reproduction. We used Mendelian randomization to estimate the causal effect of GnRH1 on IHD.…”

“…Genetic make-up is determined randomly at conception giving randomization akin to that in a randomized controlled trial, 8 and thereby unconfounded estimates. We also considered GnRH2, because it is more a driver of female sexual behavior than reproduction, 7 9 10 so GnRH1 would be expected to have more of an effect on IHD.…”