The G protein-coupled receptor TACR3 primarily mediates the signal transduction process of neurokinin B (NKB). The protein TACR3 appears in the hypothalamus and pituitary gland along with gonads and additional tissues where it chiefly controls reproductive hormone secretion and various physiological processes. Adult fertility heavily depends on TACR3 which primarily controls the hypothalamus-pituitary-gonadal axis (HPG axis).
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Physiological Role of TACR3 in Fertility
Genetic mutations within the TACR3 gene can result in hypogonadism and developmental sexual delays (HH) which stem from abnormal GnRH secretion patterns.
Promoting Secretion of Reproductive Hormones
GnRH neurons located in the arcuate nucleus (ARC) of the hypothalamus exhibit high expression levels of TACR3. Stimulation of GnRH secretion through NKB binding to TACR3 helps to control LH and FSH release. Successful ovarian and testicular functioning depends on the activity of these hormones. These hormones encourage the production of testosterone and sperm in men. TACR3 enables follicular development together with ovulation and estrogen secretion in women.
Maintaining GnRH Pulse Release
The intermittent release pattern of GnRH is fundamental to reproductive system operation. NKB-TACR3 signaling regulates the frequency of GnRH release to maintain balanced gonadotropin secretion levels. Excessive GnRH pulse frequency can result in ovarian overstimulation and disrupt ovulation while causing gonadal dysfunction. A slow GnRH pulse release can result in amenorrhea and hypogonadism in females and male infertility.
TACR3 Signaling Pathway
- NKB/TACR3 signaling axis: When NKB binds to TACR3 it triggers the Gq/11 protein signaling pathway which results in gonadotropin-releasing hormone (GnRH) secretion.
- The role of GnRH: The pituitary gland receives direct stimulation from GnRH which triggers the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) resulting in regulated gonadal function and reproductive capacity.
TACR3 Mutation and Fertility Disorders
Genetic alterations in the TACR3 gene cause developmental abnormalities in gonads and result in congenital hypogonadism (HH). Men with TACR3 gene mutations experience reduced testosterone production and impaired sperm generation which may cause infertility. Women with TACR3 gene mutations experience delayed puberty initiation along with amenorrhea and diminished estrogen production which results in fertility problems.
Potential Therapeutic Value of TACR3
The important role TACR3 plays in reproductive control suggests new therapeutic approaches with TACR3-directed drugs for reproductive disorders. Patients who struggle with insufficient GnRH secretion including those with functional hypothalamic amenorrhea could experience improved reproductive health through the use of TACR3 agonists. TACR3 antagonists can be used to treat hormone-dependent conditions including polycystic ovary syndrome (PCOS) and endometriosis.
Regulating the Secretion of Reproductive Hormones
The TACR3 gene generates the neurokinin B receptor that is primarily found on GnRH neurons situated in the hypothalamus. TACR3 NKB binding results in GnRH secretion followed by elevated levels of luteinizing hormone and follicle-stimulating hormone. The hormones that drive spermatogenesis in males support the development of ovarian follicles in females.
The Continued Role of TACR3 in Adult Fertility
TACR3 mutations demonstrate their effects during puberty but continue to hold significance throughout adulthood. The TACR3/NKB signaling pathway keeps GnRH pulsatile secretion at normal levels which controls reproductive hormone balance while affecting both gonadal function and fertility.
Potential Therapeutic Targets
The regulation of reproductive hormones by TACR3 makes it a viable target for therapeutic interventions in certain fertility disorders with either agonists or antagonists. For example:
- Agonizing TACR3: TACR3 agonists help patients with insufficient GnRH secretion achieve standard LH and FSH hormone levels.
- Antagonizing TACR3: Hormone-related conditions such as endometriosis and polycystic ovary syndrome may be treated with TACR3 antagonists.
TACR3 Regulates Important Reproductive Performance
The neurokinin receptor 3 known as TACR3 functions as a vital receptor which controls reproductive hormone secretion. The NKB-TACR3 pathway enables regulation of GnRH release which subsequently impacts gonadal function. Successful follicle development alongside ovulation and both testosterone release and sperm production depend on the proper operation of TACR3. TACR3 mutations cause reproductive disorders leading researchers to consider targeting TACR3 in upcoming fertility treatments for better success rates.
Adult fertility depends on TACR3 because this receptor regulates GnRH secretion which controls gonadal function. The occurrence of mutations in the TACR3 gene results in reproductive disorders which suggests future fertility disorder treatments may focus on TACR3 signaling pathway interventions.
Reference
- Bezzina, C., et al. Hormone profiling of adults with the TACR3 p. K286R variant and its implications in fertility. BS thesis. University of Malta. 2024.
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