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

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 - https://doi.org/10.1071/RD15357
Submitted: 14 April 2015  Accepted: 26 March 2016   Published online: 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 | 1:CAS:528:DyaK2sXhslaksrk%3D&md5=e659694858b54da63935184ef30a7e02CAS | 9038191PubMed | open url image1

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 | 1:CAS:528:DC%2BC2cXhvFGqt7vK&md5=dadd3ad3be0d03073d6de1807be62f7fCAS | 24265447PubMed | open url image1

Blomberg Jensen, M. (2014). Vitamin D and male reproduction. Nat. Rev. Endocrinol. 10, 175–186.
Vitamin D and male reproduction.CrossRef | 24419359PubMed | open url image1

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 | open url image1

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 | open url image1

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 | 1:CAS:528:DC%2BD1MXmtlGms7o%3D&md5=f1f60b73940dd2a4532c596d9fc6aa40CAS | 19176881PubMed | open url image1

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 | 1:CAS:528:DyaK38XisVylsL4%3D&md5=4dfc7360d39ce1195e79acbe91e81612CAS | 1644851PubMed | open url image1

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 | 22572998PubMed | open url image1

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 | 1:CAS:528:DC%2BD3sXjtFWgtbw%3D&md5=ae93017a3f02b67191fff74d81dcce01CAS | 12710973PubMed | open url image1

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 | 1:CAS:528:DC%2BD2cXhtVKktrrI&md5=e3ef763c0b6aa7239d97cdb1a9760da1CAS | 15589699PubMed | open url image1

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 | 1:CAS:528:DC%2BD38XhvVWmsrc%3D&md5=c8be492d6de1c5dd80399791081e94f2CAS | 11893522PubMed | open url image1

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 | 16380576PubMed | open url image1

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 | 1:CAS:528:DC%2BD3MXjsFCqsbs%3D&md5=509b15267e37f8ed617a49f76aa8c4d1CAS | open url image1

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 | 1:CAS:528:DC%2BD3MXhsFCjtLc%3D&md5=1a5f4964840590373dc7244a90047e45CAS | 11237011PubMed | open url image1

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 | 25077092PubMed | open url image1

Lips, P. (2006). Vitamin D physiology. Prog. Biophys. Mol. Biol. 92, 4–8.
Vitamin D physiology.CrossRef | 1:CAS:528:DC%2BD28XlsFKrsbo%3D&md5=328d3db1dd384832d9937019f5287a88CAS | 16563471PubMed | open url image1

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 | 1:CAS:528:DyaL2cXktFyjtrk%3D&md5=49e841221919e07f106ec7ccd31b513cCAS | 6325946PubMed | open url image1

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 | 1:CAS:528:DyaK2MXptVyntbg%3D&md5=afef63ae372c71b5fc2fed43e7540a52CAS | 8570021PubMed | open url image1

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 | 1:CAS:528:DC%2BC38XotF2ntr8%3D&md5=5829f67c64c27cb40db6bcd2f550e179CAS | 22457243PubMed | open url image1

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 | 1:CAS:528:DC%2BD1MXhtVOmurjO&md5=e6adef548f9fd331a96c86eeae9d473eCAS | 19710457PubMed | open url image1

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 | 1:CAS:528:DC%2BC3cXht1aqt73N&md5=9e56798e12cb24747d7605fff581de61CAS | 20682787PubMed | open url image1

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 | 1:CAS:528:DC%2BD1cXotF2ktbs%3D&md5=a5708f82ff3d8456f327665e2d788222CAS | 18503256PubMed | open url image1

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 | 1:CAS:528:DC%2BD3MXkslWlsrY%3D&md5=ad97db154c15df61380d8490e4240551CAS | 11416220PubMed | open url image1

Paoletti, P. (2011). Molecular basis of NMDA receptor functional diversity. Eur. J. Neurosci. 33, 1351–1365.
Molecular basis of NMDA receptor functional diversity.CrossRef | 21395862PubMed | open url image1

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 | 1:CAS:528:DC%2BD28Xms1Ortg%3D%3D&md5=aa5861b1c68cb143a4f6b835bd2b2f96CAS | 16388117PubMed | open url image1

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 | 1:CAS:528:DyaE3cXhtVChsA%3D%3D&md5=1107e6e42e747338b44ecfd07972aae3CAS | 4310770PubMed | open url image1

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 | 11916540PubMed | open url image1

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 | 1:CAS:528:DyaK2MXnsFGmu7o%3D&md5=63e95414a57d7de8c362288754c0d3eeCAS | 7555599PubMed | open url image1

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 | 1:CAS:528:DC%2BD2cXnvVOnt78%3D&md5=6c481bc9d5a5f995c8a679c6d11903ffCAS | 15452575PubMed | open url image1

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 | open url image1

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 | 1:CAS:528:DyaL38XhtlKrsb0%3D&md5=ea20b057fca6a5f53f8a359cabd94c72CAS | 6977846PubMed | open url image1

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 | 18346069PubMed | open url image1

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 | 1:CAS:528:DyaL1MXktVSrsrg%3D&md5=919a781ed11e7030fc185cc35526bb7bCAS | open url image1

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 | 1:CAS:528:DyaK1MXnt1Kr&md5=bd09ebe8a5fdb1bd4707eb5920080c88CAS | 9852048PubMed | open url image1

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 | 1:CAS:528:DyaK1cXmt1entbo%3D&md5=89a874269cfc0398ac7631893b19af41CAS | 9757035PubMed | open url image1

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 | 1:CAS:528:DyaL2cXktFyiu7g%3D&md5=a9fc51657794ac5e311c439d06d59d25CAS | 6327237PubMed | open url image1

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 | 1:CAS:528:DC%2BC3cXhtlCnsLY%3D&md5=ab0bab5f320855731d3f35da84e4a3b7CAS | 19951695PubMed | open url image1

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 | 25506316PubMed | open url image1

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 | 1:CAS:528:DyaK2sXkvFCht74%3D&md5=a391c574661154195c9b5c6c97253682CAS | 9241280PubMed | open url image1

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 | 1:CAS:528:DC%2BC38XhtlSnsb3I&md5=eabc17d28b8e7e77bcbb8f8b9888e5a3CAS | 22743040PubMed | open url image1

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 | open url image1



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