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http://dx.doi.org/10.4062/biomolther.2020.027

Epigenetically Upregulated T-Type Calcium Channels Contribute to Abnormal Proliferation of Embryonic Neural Progenitor Cells Exposed to Valproic Acid  

Kim, Ji-Woon (Departments of Pharmacology and Advanced Translational Medicine, School of Medicine, Konkuk University)
Oh, Hyun Ah (Departments of Pharmacology and Advanced Translational Medicine, School of Medicine, Konkuk University)
Kim, Sung Rae (College of Pharmacy, Chung-Ang University)
Ko, Mee Jung (Departments of Pharmacology and Advanced Translational Medicine, School of Medicine, Konkuk University)
Seung, Hana (Departments of Pharmacology and Advanced Translational Medicine, School of Medicine, Konkuk University)
Lee, Sung Hoon (College of Pharmacy, Chung-Ang University)
Shin, Chan Young (Departments of Pharmacology and Advanced Translational Medicine, School of Medicine, Konkuk University)
Publication Information
Biomolecules & Therapeutics / v.28, no.5, 2020 , pp. 389-396 More about this Journal
Abstract
Valproic acid is a clinically used mood stabilizer and antiepileptic drug. Valproic acid has been suggested as a teratogen associated with the manifestation of neurodevelopmental disorders, such as fetal valproate syndrome and autism spectrum disorders, when taken during specific time window of pregnancy. Previous studies proposed that prenatal exposure to valproic acid induces abnormal proliferation and differentiation of neural progenitor cells, presumably by inhibiting histone deacetylase and releasing the condensed chromatin structure. Here, we found valproic acid up-regulates the transcription of T-type calcium channels by inhibiting histone deacetylase in neural progenitor cells. The pharmacological blockade of T-type calcium channels prevented the increased proliferation of neural progenitor cells induced by valproic acid. Differentiated neural cells from neural progenitor cells treated with valproic acid displayed increased levels of calcium influx in response to potassium chloride-induced depolarization. These results suggest that prenatal exposure to valproic acid up-regulates T-type calcium channels, which may contribute to increased proliferation of neural progenitor cells by inducing an abnormal calcium response and underlie the pathogenesis of neurodevelopmental disorders.
Keywords
Valproic acid; Embryonic cortical brain; Neural progenitor cells; Epigenetic regulation; Proliferation; T-type calcium channels;
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1 Iftinca, M. C. and Zamponi, G. W. (2009) Regulation of neuronal T-type calcium channels. Trends Pharmacol. Sci. 30, 32-40.   DOI
2 Khosravani, H., Altier, C., Simms, B., Hamming, K. S., Snutch, T. P., Mezeyova, J., McRory, J. E. and Zamponi, G. W. (2004) Gating effects of mutations in the Cav3.2 T-type calcium channel associated with childhood absence epilepsy. J. Biol. Chem. 279, 9681-9684.   DOI
3 Khosravani, H., Bladen, C., Parker, D. B., Snutch, T. P., McRory, J. E. and Zamponi, G. W. (2005) Effects of Cav3.2 channel mutations linked to idiopathic generalized epilepsy. Ann. Neurol. 57, 745-749.   DOI
4 Kim, J. W., Oh, H. A., Lee, S. H., Kim, K. C., Eun, P. H., Ko, M. J., Gonzales, E. L. T., Seung, H., Kim, S., Bahn, G. H. and Shin, C. Y. (2018) T-type calcium channels are required to maintain viability of neural progenitor cells. Biomol. Ther. (Seoul) 26, 439-445.   DOI
5 Kim, J. W., Park, K., Kang, R. J., Gonzales, E. L. T., Kim, D. G., Oh, H. A., Seung, H., Ko, M. J., Kwon, K. J., Kim, K. C., Lee, S. H., Chung, C. and Shin, C. Y. (2019) Pharmacological modulation of AMPA receptor rescues social impairments in animal models of autism. Neuropsychopharmacology 44, 314-323.   DOI
6 Kim, J. W., Seung, H., Kim, K. C., Gonzales, E. L. T., Oh, H. A., Yang, S. M., Ko, M. J., Han, S. H., Banerjee, S. and Shin, C. Y. (2017) Agmatine rescues autistic behaviors in the valproic acid-induced animal model of autism. Neuropharmacology 113, 71-81.   DOI
7 Kim, J. W., Seung, H., Kwon, K. J., Ko, M. J., Lee, E. J., Oh, H. A., Choi, C. S., Kim, K. C., Gonzales, E. L., You, J. S., Choi, D. H., Lee, J., Han, S. H., Yang, S. M., Cheong, J. H., Shin, C. Y. and Bahn, G. H. (2014a) Subchronic treatment of donepezil rescues impaired social, hyperactive, and stereotypic behavior in valproic acid-induced animal model of autism. PLoS ONE 9, e104927.   DOI
8 Kozma, C. (2001) Valproic acid embryopathy: report of two siblings with further expansion of the phenotypic abnormalities and a review of the literature. Am. J. Med. Genet. 98, 168-175.   DOI
9 Kim, K. C., Kim, P., Go, H. S., Choi, C. S., Yang, S. I., Cheong, J. H., Shin, C. Y. and Ko, K. H. (2011) The critical period of valproate exposure to induce autistic symptoms in Sprague-Dawley rats. Toxicol. Lett. 201, 137-142.   DOI
10 Kim, K. C., Lee, D. K., Go, H. S., Kim, P., Choi, C. S., Kim, J. W., Jeon, S. J., Song, M. R. and Shin, C. Y. (2014b) Pax6-dependent cortical glutamatergic neuronal differentiation regulates autism-like behavior in prenatally valproic acid-exposed rat offspring. Mol. Neurobiol. 49, 512-528.   DOI
11 Lory, P., Bidaud, I. and Chemin, J. (2006) T-type calcium channels in differentiation and proliferation. Cell Calcium 40, 135-146.   DOI
12 Louhivuori, L. M., Louhivuori, V., Wigren, H. K., Hakala, E., Jansson, L. C., Nordstrom, T., Castren, M. L. and Akerman, K. E. (2013) Role of low voltage activated calcium channels in neuritogenesis and active migration of embryonic neural progenitor cells. Stem Cells Dev. 22, 1206-1219.   DOI
13 Martin, R. L., Lee, J. H., Cribbs, L. L., Perez-Reyes, E. and Hanck, D. A. (2000) Mibefradil block of cloned T-type calcium channels. J. Pharmacol. Exp. Ther. 295, 302-308.
14 Oguri, A., Tanaka, T., Iida, H., Meguro, K., Takano, H., Oonuma, H., Nishimura, S., Morita, T., Yamasoba, T., Nagai, R. and Nakajima, T. (2010) Involvement of CaV3.1 T-type calcium channels in cell proliferation in mouse preadipocytes. Am. J. Physiol. Cell Physiol. 298, C1414-C1423.   DOI
15 Ornoy, A. (2009) Valproic acid in pregnancy: how much are we endangering the embryo and fetus? Reprod. Toxicol. 28, 1-10.   DOI
16 Rodriguez-Gomez, J. A., Levitsky, K. L. and Lopez-Barneo, J. (2012) T-type Ca2+ channels in mouse embryonic stem cells: modulation during cell cycle and contribution to self-renewal. Am. J. Physiol. Cell Physiol. 302, C494-C504.   DOI
17 Chemin, J., Siquier-Pernet, K., Nicouleau, M., Barcia, G., Ahmad, A., Medina-Cano, D., Hanein, S., Altin, N., Hubert, L., Bole-Feysot, C., Fourage, C., Nitschke, P., Thevenon, J., Rio, M., Blanc, P., Vidal, C., Bahi-Buisson, N., Desguerre, I., Munnich, A., Lyonnet, S., Boddaert, N., Fassi, E., Shinawi, M., Zimmerman, H., Amiel, J., Faivre, L., Colleaux, L., Lory, P. and Cantagrel, V. (2018) De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene. Brain 141, 1998-2013.   DOI
18 Chen, Y., Lu, J., Pan, H., Zhang, Y., Wu, H., Xu, K., Liu, X., Jiang, Y., Bao, X., Yao, Z., Ding, K., Lo, W. H., Qiang, B., Chan, P., Shen, Y. and Wu, X. (2003) Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann. Neurol. 54, 239-243.   DOI
19 Cross, D. A., Alessi, D. R., Cohen, P., Andjelkovich, M. and Hemmings, B. A. (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378, 785-789.   DOI
20 Panner, A., Cribbs, L. L., Zainelli, G. M., Origitano, T. C., Singh, S. and Wurster, R. D. (2005) Variation of T-type calcium channel protein expression affects cell division of cultured tumor cells. Cell Calcium 37, 105-119.   DOI
21 Singh, B., Monteil, A., Bidaud, I., Sugimoto, Y., Suzuki, T., Hamano, S., Oguni, H., Osawa, M., Alonso, M. E., Delgado-Escueta, A. V., Inoue, Y., Yasui-Furukori, N., Kaneko, S., Lory, P. and Yamakawa, K. (2007) Mutational analysis of CACNA1G in idiopathic generalized epilepsy. Mutation in brief #962. Online. Hum. Mutat. 28, 524-525.
22 Splawski, I., Yoo, D. S., Stotz, S. C., Cherry, A., Clapham, D. E. and Keating, M. T. (2006) CACNA1H mutations in autism spectrum disorders. J. Biol. Chem. 281, 22085-22091.   DOI
23 Strom, S. P., Stone, J. L., Ten Bosch, J. R., Merriman, B., Cantor, R. M., Geschwind, D. H. and Nelson, S. F. (2010) High-density SNP association study of the 17q21 chromosomal region linked to autism identifies CACNA1G as a novel candidate gene. Mol. Psychiatry 15, 996-1005.   DOI
24 Taylor, J. T., Huang, L., Pottle, J. E., Liu, K., Yang, Y., Zeng, X., Keyser, B. M., Agrawal, K. C., Hansen, J. B. and Li, M. (2008) Selective blockade of T-type Ca2+ channels suppresses human breast cancer cell proliferation. Cancer Lett. 267, 116-124.   DOI
25 Gottlicher, M., Minucci, S., Zhu, P., Kramer, O. H., Schimpf, A., Giavara, S., Sleeman, J. P., Lo Coco, F., Nervi, C., Pelicci, P. G. and Heinzel, T. (2001) Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 20, 6969-6978.   DOI
26 Toth, A. B., Shum, A. K. and Prakriya, M. (2016) Regulation of neurogenesis by calcium signaling. Cell Calcium 59, 124-134.   DOI
27 Westmark, C. J. and Malter, J. S. (2007) FMRP mediates mGluR5-dependent translation of amyloid precursor protein. PLoS Biol. 5, e52.   DOI
28 DiLiberti, J. H., Farndon, P. A., Dennis, N. R. and Curry, C. J. (1984) The fetal valproate syndrome. Am. J. Med. Genet. 19, 473-481.   DOI
29 Ernst, W. L., Zhang, Y., Yoo, J. W., Ernst, S. J. and Noebels, J. L. (2009) Genetic enhancement of thalamocortical network activity by elevating alpha 1g-mediated low-voltage-activated calcium current induces pure absence epilepsy. J. Neurosci. 29, 1615-1625.   DOI
30 Go, H. S., Kim, K. C., Choi, C. S., Jeon, S. J., Kwon, K. J., Han, S. H., Lee, J., Cheong, J. H., Ryu, J. H., Kim, C. H., Ko, K. H. and Shin, C. Y. (2012) Prenatal exposure to valproic acid increases the neural progenitor cell pool and induces macrocephaly in rat brain via a mechanism involving the GSK-3beta/beta-catenin pathway. Neuropharmacology 63, 1028-1041.   DOI
31 Yano, S., Tokumitsu, H. and Soderling, T. R. (1998) Calcium promotes cell survival through CaM-K kinase activation of the protein-kinase-B pathway. Nature 396, 584-587.   DOI
32 Hirooka, K., Bertolesi, G. E., Kelly, M. E., Denovan-Wright, E. M., Sun, X., Hamid, J., Zamponi, G. W., Juhasz, A. E., Haynes, L. W. and Barnes, S. (2002) T-type calcium channel alpha1G and alpha1H subunits in human retinoblastoma cells and their loss after differentiation. J. Neurophysiol. 88, 196-205.   DOI
33 Huang, L., Keyser, B. M., Tagmose, T. M., Hansen, J. B., Taylor, J. T., Zhuang, H., Zhang, M., Ragsdale, D. S. and Li, M. (2004) NNC 55-0396 [(1S,2S)-2-(2-(N-[(3-benzimidazol-2-yl)propyl]-N-methylamino)ethyl)-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate dihydrochloride]: a new selective inhibitor of T-type calcium channels. J. Pharmacol. Exp. Ther. 309, 193-199.   DOI
34 Dalens, B., Raynaud, E. J. and Gaulme, J. (1980) Teratogenicity of valproic acid. J. Pediatr. 97, 332-333.
35 Williams, G., King, J., Cunningham, M., Stephan, M., Kerr, B. and Hersh, J. H. (2001) Fetal valproate syndrome and autism: additional evidence of an association. Dev. Med. Child Neurol. 43, 202-206.   DOI