Loffler S, et al reported that transcripts of neurokinin B and neurokinin 3 receptor in superovulated rat ovaries and increased number of corpora lutea as a non-specific effect of intraperitoneal agonist application.
Neurokinin B (NKB), a member of the tachykinin family, and its neurokinin 3 receptor (NK3-R) are preferentially found in the central nervous system. Others have recently reported on mRNA from this ligand-receptor system in the uterus and on NK3-R expression increasing with age. NKB and NK3-R mRNAs have also been noted in
cumulus cells and oocytes from superovulated rats. Intact ovaries before and after puberty have not been studied. In this study, we stimulated 29-day-old rats by s.c. injections with gonadotropins for estrous cycle synchronization in order to elucidate the NKB-NK3-R system's expression and function in the ovary. Simultaneously, NaCl, the NK3-R agonist (Pro(7))-NKB, the antagonist SB 218795, a neutral endopeptidase inhibitor of tachykinin degradation, were injected intraperitoneally (i.p.) for 3 1/2 consecutive days. First, we demonstrated NKB and NK3-R transcripts in one rat ovary by RT-PCR. No significant mRNA differences were noted between immature ovaries and superovulated ovaries in any of the i.p. applications. Second, the possible role of NK3-R on the ovulatory process was verified by counting corpora lutea (CL) and CL cysts in serial sections of the other ovary derived from the four different groups and embedded in paraffin wax. CL and CL cysts were noted in greater numbers in the pharmacologically treated groups than in the saline-treated group. To validate possible drug effects on the peritoneum, we additionally studied pieces of the omentum majus and retroperitoneal fat tissue. Both tissues were heavily infiltrated by granulocytes similar to a non-specific inflammatory response. The saline-treated group as well as the pharmacologically treated groups appeared to develop this unexpected side effect to a similar degree. We conclude that transcripts of NKB and NK3-R are present before and after puberty in the rat ovary and appear to be expressed at similar levels which may indicate a role for the NKB-NK3-R system in follicle growth. The effect of increased CL formation after application of the NK3-R agonist i.p. is related to a non-specific response.
NCBI Summary:
This gene belongs to a family of genes that function as receptors for tachykinins. Receptor affinities are specified by variations in the 5'-end of the sequence. The receptors belonging to this family are characterized by interactions with G proteins and 7 hydrophobic transmembrane regions. This gene encodes the receptor for the tachykinin neurokinin 3, also referred to as neurokinin B. [provided by RefSeq, Jul 2008]
General function
Receptor
Comment
Cellular localization
Plasma membrane
Comment
Randomized Controlled Trial of Neurokinin 3 Receptor Antagonist Fezolinetant for Treatment of Polycystic Ovary Syndrome. Fraser GL et al. (2021) Polycystic ovary syndrome (PCOS), a highly prevalent endocrine disorder characterized by hyperandrogenism, is the leading cause of anovulatory infertility. This proof-of-concept study evaluated clinical efficacy and safety of the neurokinin 3 (NK3) receptor antagonist fezolinetant in PCOS. This was a phase 2a, randomized, double-blind, placebo-controlled, multicenter study (EudraCT 2014-004409-34). The study was conducted at 5 European clinical centers. Women with PCOS participated in the study. Interventions included fezolinetant 60 or 180 mg/d or placebo for 12 weeks. The primary efficacy endpoint was change in total testosterone. Gonadotropins, ovarian hormones, and safety/tolerability were also assessed. Seventy-three women were randomized, and 64 participants completed the study. Adjusted mean (SE) changes in total testosterone from baseline to week 12 for fezolinetant 180 and 60 mg/d were -0.80 (0.13) and -0.39 (0.12) nmol/L versus -0.05 (0.10) nmol/L with placebo (P<0.0001 and P<0.05, respectively). Adjusted mean (SE) changes from baseline in luteinizing hormone (LH) for fezolinetant 180 and 60 mg/d were -10.17 (1.28) and -8.21 (1.18) versus -3.16 (1.04) IU/L with placebo (P<0.0001 and P=0.0022); corresponding changes in follicle-stimulating hormone (FSH) were -1.46 (0.32) and -0.92 (0.30) versus -0.57 (0.26) IU/L (P=0.0336 and P=0.3770), underpinning a dose-dependent decrease in the LH-to-FSH ratio versus placebo (P<0.001). Circulating levels of progesterone and estradiol did not change significantly versus placebo (P>0.1). Fezolinetant was well tolerated. Fezolinetant had a sustained effect to suppress hyperandrogenism and reduce the LH-to-FSH ra.//////////////////
Ovarian function
Steroid metabolism, Luteinization
Comment
Elinzanetant (NT-814), a Neurokinin 1,3 Receptor Antagonist, Reduces Estradiol and Progesterone in Healthy Women. Pawsey S et al. (2021) The ideal therapy for endometriosis (EM) and uterine fibroids (UF) would suppress estrogenic drive to the endometrium and myometrium, whilst minimizing vasomotor symptoms and bone loss associated with current treatments. An integrated neurokinin-kisspeptin system involving Substance P and neurokinin B acting at the neurokinin (NK) receptors 1 and 3, respectively, modulates reproductive hormone secretion and represents a therapeutic target. To assess the effects of the novel NK1,3 antagonist elinzanetant on reproductive hormone levels in healthy women. Randomized, single-blinded, placebo-controlled study. Thirty-three women attended for 2 consecutive menstrual cycles. In each cycle blood samples were taken on days 3/4, 9/10, 15/16 and 21/22 to measure serum reproductive hormones. In cycle 2, women were randomized to receive once daily oral elinzanetant 40, 80, 120 mg or placebo (N=8 or 9 per group). Elinzanetant dose-dependently lowered serum luteinizing hormone, estradiol (120 mg median change across cycle: -141.4 pmol/L, P=0.038) and luteal phase progesterone (120 mg change from baseline on day 21/22: -19.400 nmol/L, P=0.046). Elinzanetant 120 mg prolonged the cycle length by median of 7.0 days (P=0.023). Elinzanetant reduced the proportion of women with a luteal phase serum progesterone concentration >30 nmol/L (a concentration consistent with ovulation) in a dose-related manner in cycle 2 (P=0.002). Treatment did not produce vasomotor symptoms. NK1,3 receptor antagonism with elinzanetant dose-dependently suppressed the reproductive axis in healthy women, with the 120 mg dose lowering estradiol to potentially ideal levels for UF and EM. As such, elinzanetant may represent a novel therapy to manipulate reproductive hormone levels in women with hormone driven disorders.//////////////////
Expression regulated by
Comment
Ovarian localization
Cumulus, Granulosa, Luteal cells
Comment
Expression of neurokinin B/NK3 receptor and kisspeptin/KISS1 receptor in human granulosa cells. García-Ortega J et al. (2014) Are neurokinin B (NKB), NK3 receptor (NK3R), kisspeptin (KISS1) and kisspeptin receptor (KISS1R) expressed in human ovarian granulosa cells? The NKB/NK3R and kisspeptin/KISS1R systems are co-expressed and functionally active in ovarian granulosa cells. The NKB/NK3R and KISS1/KISS1R systems are essential for reproduction. In addition to their well-recognized role in hypothalamic neurons, these peptide systems may contribute to the control of fertility by acting directly on the gonads, but such a direct gonadal role remains largely unknown. This study analyzed matched mural granulosa cells (MGCs) and cumulus cells (CCs) collected from preovulatory follicles of oocyte donors at the time of oocyte retrieval. The samples were provided by 56 oocyte donor women undergoing ovarian stimulation treatment. Follicular fluid samples containing MGCs and cumulus-oocyte complexes were collected after transvaginal ultrasound-guided oocyte retrieval. RT-PCR, quantitative real-time PCR, immunocytochemistry and western blot were used to investigate the pattern of expression of the NKB/NK3R and KISS/KISS1R systems in MGCs and CCs. Intracellular free Ca(2+) levels, [Ca(2+)]i, in MGCs after exposure to NKB or KISS1, in the presence or not of tachykinin receptor antagonists, were also measured. NKB/NK3R and KISS1/KISS1R systems were expressed, at the mRNA and protein levels, in MGCs and CCs, with significantly higher expression in CCs. Kisspeptin increased the [Ca(2+)]i in the cytosol of human MGCs while exposure to NKB failed to induce any change in [Ca(2+)]i. However, the [Ca(2+)]i response to kisspeptin was reduced in the presence of NKB. The inhibitory effect of NKB was only partially mimicked by the NK3R agonist, senktide and marginally suppressed by the NK3R-selective antagonist SB 222200. Yet, a cocktail of antagonists selective for the NK1, NK2 and NK3 receptors blocked the effect of NKB. The granulosa and cumulus cells were obtained from oocyte donors undergoing ovarian stimulation, which in comparison with natural cycles, may have affected gene and protein expression in granulosa cells. Our data demonstrate that, in addition to their indispensable effects at the central nervous system, the NKB/NK3R and kisspeptin/KISS1R systems are co-expressed and are functionally active in non-neuronal reproductive cells of the female gonads, the ovarian granulosa cells. This work was supported by grants from Ministerio de Economía y Competitividad (CTQ2011-25564 and BFI2011-25021) and Junta de Andalucía (P08-CVI-04185), Spain. J.G.-O., F.M.P., M.F.-S., N.P., A.C.-R., T.A.A., M.H., M.R., M.T.-S. and L.C. have nothing to declare.//////////////////
Follicle stages
Corpus luteum
Comment
Coexpression of preprotachykinin A and B transcripts in the bovine corpus luteum and evidence for functional neurokinin receptor activity in luteal endothelial cells and ovarian macrophages Brylla E, et al .
Nonneuronal cell sources of tachykinins, such as substance P (SP) and neurokinin B (NKB), have been demonstrated in leukocytes, endothelial cells and endocrine cells, and may play a role in corpus luteum (CL) development. For this reason, we analyzed mRNA presence for the two tachykinin precursors together with the neurokinin-1 receptor and the neurokinin-3 receptor (NK-1R and NK-3R, preferred by SP and NKB, respectively) in bovine CL at various stages in the luteal phase. Using the RT-PCR technique, we detected coexpression for the preprotachykinin A gene (PPT-A), which encodes SP and neurokinin A (NKA), and the preprotachykinin B gene (PPT-B) for NKB in the CL at the development, secretion and regression stages. Coexpression was also noted for NK-1R and NK-3R gene transcripts. Cultures of endothelial cells (ECs) derived from bovine CL expressed NK-1R and NK-3R mRNA, as did ovarian macrophages. Agonist treatment induced a stronger intracellular calcium ([Ca(2+)](i)) increase after activation of NK-1R compared to NK-3R, a result that we verified by calcium imaging. This is the first evidence for functional tachykinin receptor activity in luteal ECs and ovarian macrophages from bovine CL.