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Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology
RESEARCH ARTICLE

Non-genomic action of vitamin D3 on N-methyl-D-aspartate and kainate receptor-mediated actions in juvenile gonadotrophin-releasing hormone neurons

Pravin Bhattarai A , Janardhan P. Bhattarai A , Min Sun Kim B C and Seong Kyu Han A C
+ Author Affiliations
- Author Affiliations

A Department of Oral Physiology, School of Dentistry and Institute of Oral Bioscience, Chonbuk National University, Duckjin Dong, Jeonju, Jeonbuk 561-756, South Korea.

B Department of Pediatrics, Chonbuk National University Medical School, and Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Institute of Chonbuk National University Hospital, Duckjin Dong, Jeonju, Jeonbuk 561-756, South Korea.

C Corresponding authors. Emails: skhan@jbnu.ac.kr; 082kiki@naver.com

Reproduction, Fertility and Development 29(6) 1231-1238 https://doi.org/10.1071/RD15357
Submitted: 14 April 2015  Accepted: 26 March 2016   Published: 26 May 2016

Abstract

Vitamin D is a versatile signalling molecule that plays a critical role in calcium homeostasis. There are several studies showing the genomic action of vitamin D in the control of reproduction; however, the quick non-genomic action of vitamin D at the hypothalamic level is not well understood. Therefore, to investigate the effect of vitamin D on juvenile gonadotrophin-releasing hormone (GnRH) neurons, excitatory neurotransmitter receptor agonists N-methyl-D-aspartate (NMDA, 30 μM) and kainate (10 μM) were applied in the absence or in the presence of vitamin D3 (VitaD3, 10 nM). The NMDA-mediated responses were decreased by VitaD3 in the absence and in the presence of tetrodotoxin (TTX), a sodium-channel blocker, with the mean relative inward current being 0.56 ± 0.07 and 0.66 ± 0.07 (P < 0.05), respectively. In addition, VitaD3 induced a decrease in the frequency of gamma-aminobutyric acid mediated (GABAergic) spontaneous postsynaptic currents and spontaneous postsynaptic currents induced by NMDA application with a mean relative frequency of 0.595 ± 0.07 and 0.56 ± 0.09, respectively. Further, VitaD3 decreased the kainate-induced inward currents in the absence and in the presence of TTX with a relative inward current of 0.64 ± 0.06 and 0.68 ± 0.06, respectively (P < 0.05). These results suggest that VitaD3 has a non-genomic action and partially inhibits the NMDA and kainate receptor-mediated actions of GnRH neurons, suggesting that VitaD3 may regulate the hypothalamic–pituitary–gonadal (HPG) axis at the time of pubertal development.

Additional keywords: brain slice, electrophysiology, excitatory neurotransmitters, HPG axis, patch clamp.


References

Barsony, J., Renyi, I., and McKoy, W. (1997). Subcellular distribution of normal and mutant vitamin D receptors in living cells. Studies with a novel fluorescent ligand. J. Biol. Chem. 272, 5774–5782.
Subcellular distribution of normal and mutant vitamin D receptors in living cells. Studies with a novel fluorescent ligand.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2sXhslaksrk%3D&md5=e659694858b54da63935184ef30a7e02CAS | 9038191PubMed |

Bhattarai, J. P., Roa, J., Herbison, A. E., and Han, S. K. (2014). Serotonin acts through 5–HT1 and 5–HT2 receptors to exert biphasic actions on GnRH neuron excitability in the mouse. Endocrinology 155, 513–524.
Serotonin acts through 5–HT1 and 5–HT2 receptors to exert biphasic actions on GnRH neuron excitability in the mouse.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXhvFGqt7vK&md5=dadd3ad3be0d03073d6de1807be62f7fCAS | 24265447PubMed |

Blomberg Jensen, M. (2014). Vitamin D and male reproduction. Nat. Rev. Endocrinol. 10, 175–186.
Vitamin D and male reproduction.Crossref | GoogleScholarGoogle Scholar | 24419359PubMed |

Bouillon, R., Verstuyf, A., Branisteanu, D., Waer, M., and Mathieu, C. (1995). Immune modulation by vitamin D analogues in the prevention of autoimmune diseases. Verh. K. Acad. Geneeskd. Belg. 57, 371–385, discussion 385–387.
| 1:STN:280:DyaK287kvVehtA%3D%3D&md5=2d9a137c8d1681c421925c0a131512b0CAS | 8571669PubMed |

Brewer, L. D., Thibault, V., Chen, K. C., Langub, M. C., Landfield, P. W., and Porter, N. M. (2001). Vitamin D hormone confers neuroprotection in parallel with downregulation of L-type calcium channel expression in hippocampal neurons. J. Neurosci. 21, 98–108.
| 1:CAS:528:DC%2BD3MXmtVOhtA%3D%3D&md5=9441d0d599d7776d22d04c6f8e86c691CAS | 11150325PubMed |

Christian, C. A., Pielecka-Fortuna, J., and Moenter, S. M. (2009). Oestradiol suppresses glutamatergic transmission to gonadotrophin-releasing hormone neurons in a model of negative feedback in mice. Biol. Reprod. 80, 1128–1135.
Oestradiol suppresses glutamatergic transmission to gonadotrophin-releasing hormone neurons in a model of negative feedback in mice.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXmtlGms7o%3D&md5=f1f60b73940dd2a4532c596d9fc6aa40CAS | 19176881PubMed |

de Boland, A. R., and Nemere, I. (1992). Rapid actions of vitamin D compounds. J. Cell. Biochem. 49, 32–36.
Rapid actions of vitamin D compounds.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK38XisVylsL4%3D&md5=4dfc7360d39ce1195e79acbe91e81612CAS | 1644851PubMed |

Dicken, C. L., Israel, D. D., Davis, J. B., Sun, Y., Shu, J., Hardin, J., and Neal-Perry, G. (2012). Peripubertal vitamin D(3) deficiency delays puberty and disrupts the oestrous cycle in adult female mice. Biol. Reprod. 87, 51.
Peripubertal vitamin D(3) deficiency delays puberty and disrupts the oestrous cycle in adult female mice.Crossref | GoogleScholarGoogle Scholar | 22572998PubMed |

Eyles, D., Brown, J., Mackay-Sim, A., McGrath, J., and Feron, F. (2003). Vitamin D3 and brain development. Neuroscience 118, 641–653.
Vitamin D3 and brain development.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXjtFWgtbw%3D&md5=ae93017a3f02b67191fff74d81dcce01CAS | 12710973PubMed |

Eyles, D. W., Smith, S., Kinobe, R., Hewison, M., and McGrath, J. J. (2005). Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J. Chem. Neuroanat. 29, 21–30.
Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXhtVKktrrI&md5=e3ef763c0b6aa7239d97cdb1a9760da1CAS | 15589699PubMed |

Garcion, E., Wion-Barbot, N., Montero-Menei, C. N., Berger, F., and Wion, D. (2002). New clues about vitamin D functions in the nervous system. Trends Endocrinol. Metab. 13, 100–105.
New clues about vitamin D functions in the nervous system.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38XhvVWmsrc%3D&md5=c8be492d6de1c5dd80399791081e94f2CAS | 11893522PubMed |

Garland, C. F., Garland, F. C., Gorham, E. D., Lipkin, M., Newmark, H., Mohr, S. B., and Holick, M. F. (2006). The role of vitamin D in cancer prevention. Am. J. Public Health 96, 252–261.
The role of vitamin D in cancer prevention.Crossref | GoogleScholarGoogle Scholar | 16380576PubMed |

Hsu, S., O’Connell, P. J., Klyachko, V. A., Badminton, M. N., Thomson, A. W., Jackson, M. B., Clapham, D. E., and Ahern, G. P. (2001). Fundamental Ca2+ signalling mechanisms in mouse dendritic cells: CRAC is the major Ca2+ entry pathway. J. Immunol. 166, 6126–6133.
Fundamental Ca2+ signalling mechanisms in mouse dendritic cells: CRAC is the major Ca2+ entry pathway.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXjsFCqsbs%3D&md5=509b15267e37f8ed617a49f76aa8c4d1CAS |

Lander, E. S., Linton, L. M., Birren, B., Nusbaum, C., Zody, M. C., Baldwin, J., Devon, K., Dewar, K., Doyle, M., FitzHugh, W., et al. (2001). Initial sequencing and analysis of the human genome. Nature 409, 860–921.
Initial sequencing and analysis of the human genome.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXhsFCjtLc%3D&md5=1a5f4964840590373dc7244a90047e45CAS | 11237011PubMed |

Lee, H. S., Kim, Y. J., Shim, Y. S., Jeong, H. R., Kwon, E., and Hwang, J. S. (2014). Associations between serum vitamin D levels and precocious puberty in girls. Ann. Pediatr. Endocrinol. Metab. 19, 91–95.
Associations between serum vitamin D levels and precocious puberty in girls.Crossref | GoogleScholarGoogle Scholar | 25077092PubMed |

Lips, P. (2006). Vitamin D physiology. Prog. Biophys. Mol. Biol. 92, 4–8.
Vitamin D physiology.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XlsFKrsbo%3D&md5=328d3db1dd384832d9937019f5287a88CAS | 16563471PubMed |

Mayer, M. L., Westbrook, G. L., and Guthrie, P. B. (1984). Voltage-dependent block by Mg2+ of NMDA responses in spinal-cord neurones. Nature 309, 261–263.
Voltage-dependent block by Mg2+ of NMDA responses in spinal-cord neurones.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL2cXktFyjtrk%3D&md5=49e841221919e07f106ec7ccd31b513cCAS | 6325946PubMed |

Mori, H., and Mishina, M. (1995). Structure and function of the NMDA receptor channel. Neuropharmacology 34, 1219–1237.
Structure and function of the NMDA receptor channel.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2MXptVyntbg%3D&md5=afef63ae372c71b5fc2fed43e7540a52CAS | 8570021PubMed |

Motiwala, S. R., and Wang, T. J. (2012). Vitamin D and cardiovascular risk. Curr. Hypertens. Rep. 14, 209–218.
Vitamin D and cardiovascular risk.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XotF2ntr8%3D&md5=5829f67c64c27cb40db6bcd2f550e179CAS | 22457243PubMed |

Nashold, F. E., Spach, K. M., Spanier, J. A., and Hayes, C. E. (2009). Oestrogen controls vitamin D3-mediated resistance to experimental autoimmune encephalomyelitis by controlling vitamin D3 metabolism and receptor expression. J. Immunol. 183, 3672–3681.
Oestrogen controls vitamin D3-mediated resistance to experimental autoimmune encephalomyelitis by controlling vitamin D3 metabolism and receptor expression.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXhtVOmurjO&md5=e6adef548f9fd331a96c86eeae9d473eCAS | 19710457PubMed |

Nemere, I., Garbi, N., Hammerling, G. J., and Khanal, R. C. (2010). Intestinal cell calcium uptake and the targeted knockout of the 1,25D3-MARRS (membrane-associated, rapid-response steroid-binding) receptor/PDIA3/Erp57. J. Biol. Chem. 285, 31859–31866.
Intestinal cell calcium uptake and the targeted knockout of the 1,25D3-MARRS (membrane-associated, rapid-response steroid-binding) receptor/PDIA3/Erp57.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXht1aqt73N&md5=9e56798e12cb24747d7605fff581de61CAS | 20682787PubMed |

Oudshoorn, C., Mattace-Raso, F. U., van der Velde, N., Colin, E. M., and van der Cammen, T. J. (2008). Higher serum vitamin D3 levels are associated with better cognitive test performance in patients with Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 25, 539–543.
Higher serum vitamin D3 levels are associated with better cognitive test performance in patients with Alzheimer’s disease.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXotF2ktbs%3D&md5=a5708f82ff3d8456f327665e2d788222CAS | 18503256PubMed |

Panda, D. K., Miao, D., Tremblay, M. L., Sirois, J., Farookhi, R., Hendy, G. N., and Goltzman, D. (2001). Targeted ablation of the 25-hydroxyvitamin D 1alpha-hydroxylase enzyme: evidence for skeletal, reproductive and immune dysfunction. Proc. Natl. Acad. Sci. USA 98, 7498–7503.
Targeted ablation of the 25-hydroxyvitamin D 1alpha-hydroxylase enzyme: evidence for skeletal, reproductive and immune dysfunction.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXkslWlsrY%3D&md5=ad97db154c15df61380d8490e4240551CAS | 11416220PubMed |

Paoletti, P. (2011). Molecular basis of NMDA receptor functional diversity. Eur. J. Neurosci. 33, 1351–1365.
Molecular basis of NMDA receptor functional diversity.Crossref | GoogleScholarGoogle Scholar | 21395862PubMed |

Parent, A. S., Matagne, V., and Bourguignon, J. P. (2005). Control of puberty by excitatory amino acid neurotransmitters and its clinical implications. Endocrine 28, 281–286.
Control of puberty by excitatory amino acid neurotransmitters and its clinical implications.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28Xms1Ortg%3D%3D&md5=aa5861b1c68cb143a4f6b835bd2b2f96CAS | 16388117PubMed |

Ponchon, G., Kennan, A. L., and DeLuca, H. F. (1969). “Activation” of vitamin D by the liver. J. Clin. Invest. 48, 2032–2037.
“Activation” of vitamin D by the liver.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaE3cXhtVChsA%3D%3D&md5=1107e6e42e747338b44ecfd07972aae3CAS | 4310770PubMed |

Rodríguez-Martínez, M. A., and García-Cohen, E. C. (2002). Role of Ca2+ and vitamin D in the prevention and treatment of osteoporosis. Pharmacol. Ther. 93, 37–49.
Role of Ca2+ and vitamin D in the prevention and treatment of osteoporosis.Crossref | GoogleScholarGoogle Scholar | 11916540PubMed |

Scragg, R., Holdaway, I., Singh, V., Metcalf, P., Baker, J., and Dryson, E. (1995). Serum 25-hydroxyvitamin D3 levels decreased in impaired glucose tolerance and diabetes mellitus. Diabetes Res. Clin. Pract. 27, 181–188.
Serum 25-hydroxyvitamin D3 levels decreased in impaired glucose tolerance and diabetes mellitus.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2MXnsFGmu7o%3D&md5=63e95414a57d7de8c362288754c0d3eeCAS | 7555599PubMed |

Sisk, C. L., and Foster, D. L. (2004). The neural basis of puberty and adolescence. Nat. Neurosci. 7, 1040–1047.
The neural basis of puberty and adolescence.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXnvVOnt78%3D&md5=6c481bc9d5a5f995c8a679c6d11903ffCAS | 15452575PubMed |

Spergel, D. J., Kruth, U., Hanley, D. F., Sprengel, R., and Seeburg, P. H. (1999). GABA- and glutamate-activated channels in green fluorescent protein-tagged gonadotrophin-releasing hormone neurons in transgenic mice. J. Neurosci. 19, 2037–2050.
| 1:CAS:528:DyaK1MXhslKmtrs%3D&md5=4682b9c9b97cb5ff5c79a5a45a15ef86CAS | 10066257PubMed |

Stumpf, W. E., Sar, M., Clark, S. A., and DeLuca, H. F. (1982). Brain target sites for 1,25-dihydroxyvitamin D3. Science 215, 1403–1405.
Brain target sites for 1,25-dihydroxyvitamin D3.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL38XhtlKrsb0%3D&md5=ea20b057fca6a5f53f8a359cabd94c72CAS | 6977846PubMed |

Turner, M. K., Hooten, W. M., Schmidt, J. E., Kerkvliet, J. L., Townsend, C. O., and Bruce, B. K. (2008). Prevalence and clinical correlates of vitamin D inadequacy among patients with chronic pain. Pain Med. 9, 979–984.
Prevalence and clinical correlates of vitamin D inadequacy among patients with chronic pain.Crossref | GoogleScholarGoogle Scholar | 18346069PubMed |

Urbanski, H. F., and Ojeda, S. R. (1987–1988). Neuroendocrine mechanisms controlling the onset of female puberty. Reprod. Toxicol. 1, 129–138.
Neuroendocrine mechanisms controlling the onset of female puberty.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL1MXktVSrsrg%3D&md5=919a781ed11e7030fc185cc35526bb7bCAS |

Vazquez, G., de Boland, A. R., and Boland, R. L. (1998). 1Alpha,25-dihydroxy-vitamin-D3-induced store-operated Ca2+ influx in skeletal muscle cells. Modulation by phospholipase C, protein kinase C and tyrosine kinases. J. Biol. Chem. 273, 33954–33960.
1Alpha,25-dihydroxy-vitamin-D3-induced store-operated Ca2+ influx in skeletal muscle cells. Modulation by phospholipase C, protein kinase C and tyrosine kinases.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXnt1Kr&md5=bd09ebe8a5fdb1bd4707eb5920080c88CAS | 9852048PubMed |

Veenstra, T. D., Prufer, K., Koenigsberger, C., Brimijoin, S. W., Grande, J. P., and Kumar, R. (1998). 1,25-Dihydroxyvitamin D3 receptors in the central nervous system of the rat embryo. Brain Res. 804, 193–205.
1,25-Dihydroxyvitamin D3 receptors in the central nervous system of the rat embryo.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXmt1entbo%3D&md5=89a874269cfc0398ac7631893b19af41CAS | 9757035PubMed |

Walters, M. R. (1984). 1,25-dihydroxyvitamin D3 receptors in the seminiferous tubules of the rat testis increase at puberty. Endocrinology 114, 2167–2174.
1,25-dihydroxyvitamin D3 receptors in the seminiferous tubules of the rat testis increase at puberty.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL2cXktFyiu7g%3D&md5=a9fc51657794ac5e311c439d06d59d25CAS | 6327237PubMed |

Wang, Y., Becklund, B. R., and DeLuca, H. F. (2010). Identification of a highly specific and versatile vitamin D receptor antibody. Arch. Biochem. Biophys. 494, 166–177.
Identification of a highly specific and versatile vitamin D receptor antibody.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXhtlCnsLY%3D&md5=ab0bab5f320855731d3f35da84e4a3b7CAS | 19951695PubMed |

Watanabe, M., Fukuda, A., and Nabekura, J. (2014). The role of GABA in the regulation of GnRH neurons. Front. Neurosci. 8, 387.
The role of GABA in the regulation of GnRH neurons.Crossref | GoogleScholarGoogle Scholar | 25506316PubMed |

Yoshizawa, T., Handa, Y., Uematsu, Y., Takeda, S., Sekine, K., Yoshihara, Y., Kawakami, T., Arioka, K., Sato, H., Uchiyama, Y., Masushige, S., Fukamizu, A., Matsumoto, T., and Kato, S. (1997). Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat. Genet. 16, 391–396.
Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2sXkvFCht74%3D&md5=a391c574661154195c9b5c6c97253682CAS | 9241280PubMed |

Zanatta, L., Goulart, P. B., Goncalves, R., Pierozan, P., Winkelmann-Duarte, E. C., Woehl, V. M., Pessoa-Pureur, R., Silva, F. R., and Zamoner, A. (2012). 1Alpha,25-dihydroxyvitamin D(3) mechanism of action: modulation of L-type calcium channels leading to calcium uptake and intermediate filament phosphorylation in cerebral cortex of young rats. Biochim. Biophys. Acta 1823, 1708–1719.
1Alpha,25-dihydroxyvitamin D(3) mechanism of action: modulation of L-type calcium channels leading to calcium uptake and intermediate filament phosphorylation in cerebral cortex of young rats.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XhtlSnsb3I&md5=eabc17d28b8e7e77bcbb8f8b9888e5a3CAS | 22743040PubMed |

Zehnder, D., Bland, R., Williams, M. C., McNinch, R. W., Howie, A. J., Stewart, P. M., and Hewison, M. (2001). Extrarenal expression of 25-hydroxyvitamin D(3)-1alpha-hydroxylase. J. Clin. Endocrinol. Metab. 86, 888–894.
| 1:CAS:528:DC%2BD3MXht1Knurw%3D&md5=cc519f58808e657f493e59e02108af42CAS | 11158062PubMed |