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PLoS One
2010 Nov 03;511:e13817. doi: 10.1371/journal.pone.0013817.
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Ionotropic glutamate receptor AMPA 1 is associated with ovulation rate.
Sugimoto M
,
Sasaki S
,
Watanabe T
,
Nishimura S
,
Ideta A
,
Yamazaki M
,
Matsuda K
,
Yuzaki M
,
Sakimura K
,
Aoyagi Y
,
Sugimoto Y
.
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Ionotropic glutamate receptors mediate most excitatory neurotransmission in the central nervous system by opening ion channels upon the binding of glutamate. Despite the essential roles of glutamate in the control of reproduction and anterior pituitary hormone secretion, there is a limited understanding of how glutamate receptors control ovulation. Here we reveal the function of the ionotropic glutamate receptor AMPA-1 (GRIA1) in ovulation. Based on a genome-wide association study in Bos taurus, we found that ovulation rate is influenced by a variation in the N-terminal leucine/isoleucine/valine-binding protein (LIVBP) domain of GRIA1, in which serine is replaced by asparagine. GRIA1(Asn) has a weaker affinity to glutamate than GRIA1(Ser), both in Xenopus oocytes and in the membrane fraction of bovine brain. This single amino acid substitution leads to the decreased release of gonadotropin-releasing hormone (GnRH) in immortalized hypothalamic GT1-7 cells. Cows with GRIA1(Asn) have a slower luteinizing hormone (LH) surge than cows with GRIA1(Ser). In addition, cows with GRIA1(Asn) possess fewer immature ovarian follicles before superovulation and have a lower response to hormone treatment than cows with GRIA1(Ser). Our work identified that GRIA1 is a critical mediator of ovulation and that GRIA1 might be a useful target for reproductive therapy.
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21072200
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Figure 1. The average number of ova and embryos collected per superovulation over five treatments.
Figure 2. GRIA1 is associated with ovulation rate in cattle.(A) Association signals with ovulation rate on chromosome 7 using plots of the P values for Fisher's exact test after estimating haplotypes of consecutive marker pairs by expectation-maximization algorithm. The red line represents the threshold for genome-wise significance after correction using the Bonferroni correction for multiple comparisons. (B) The map of markers (blue circles) and a gene (black line) found in the candidate region of chromosome 7. The red circle represents an SNP found in the gene. (C) Schematic illustration of GRIA1 that harbors 4 transmembrane (TM) domains and the LIVBP domain, which includes alignment of partial mammalian amino acid sequences. (D) The average number of ova and embryos collected per superovulation of S/S, S/N, and N/N cows over five treatments. Data are presented as mean ± SEM. P values were calculated by Student's t-test.
Figure 3. S306N in GRIA1 affects ligand affinity.(A) Saturation curves for [3H] AMPA binding to brain of S/S (red, n = 3), S/N (green, n = 3), and N/N cows (blue, n = 3). Data are presented as mean ± SEM. a indicates p<0.05 by Student's t-test between S/S and N/N cows. (B) Dose-response curves of Xenopus oocytes expressing GRIA1Ser (red, n = 10) or GRIA1Asn (blue, n = 9). Normalized response means current normalized to the current evoked by a saturating dose of glutamate. Data are presented as mean ± SEM. a–e indicate p<0.05 by Student's t-test between GRIA1Ser and GRIA1Asn. (C) Dose-response curves of Xenopus oocytes expressing GRIA1Ser (red, n = 8) or GRIA1Asn (blue, n = 8) with GRIA2. Data are presented as mean ± SEM. a–d indicate p<0.05 by Student's t-test between GRIA1Ser and GRIA1Asn. (D) I–V relationships of oocytes expressing GRIA1Ser (red broken line; n = 4), GRIA1Ser with GRIA2 (red line; n = 5), GRIA1Asn (blue broken line; n = 4), and GRIA1Asn with GRIA2 (blue line; n = 5). Each I–V relationship was normalized to the current obtained at −70 mV. Data are presented as mean ± SEM.
Figure 4. S306N in GRIA1 affects hormone release.(A) Schematic of ovulation control. (B) The concentration of GnRH released from GT1-7 cells expressing GRIA1Ser (red) or GRIA1Asn (blue). Data are presented as mean ± SEM (n = 3 each). P values were calculated by Student's t-test. (C) Representative immunoblots with anti-HA (GRIA1) and anti-actin (control) antibody. (D) The protocol for superovulation in cattle. (E–F) The concentration of FSH (E) and LH (F) in the serum of S/S (red, n = 6), S/N (green, n = 5), and N/N cows (blue, n = 4) during superovulation. Data are presented as mean ± SEM. a and b indicate p<0.05 by Student's t-test between S/S and N/N cows.
Figure 5. S306N in GRIA1 affects ovulation.(A) Representative photo of an ovary of an S/S cow at Day 13 by ultrasound scanning. Mature follicles (φ>10 mm) were recognizable. (B–D) The average number of immature follicles (B, φ = 2–5 mm), maturing follicles (C, φ = 6–9 mm), and mature follicles (D, φ>10 mm) observed by ultrasound scanning of S/S (red, n = 6), S/N (green, n = 5), and N/N cows (blue, n = 4) during superovulation. Data are presented as mean ± SEM. a and b indicate p<0.05 by Student's t-test between S/S and N/N cows. (E) The average number of CL of S/S (red, n = 6), S/N (green, n = 5), and N/N cows (blue, n = 4) after superovulation. Data are presented as mean ± SEM.
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