Biomolecules & Therapeutics  https://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
Ji-Woon Kim1, Hyun Ah Oh1, Sung Rae Kim2, Mee Jung Ko1, Hana Seung1, Sung Hoon Lee2,* and Chan Young Shin1,*
1Departments of Pharmacology and Advanced Translational Medicine, School of Medicine, Konkuk University, Seoul 05029,
2College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
E-mail: sunghoonlee@cau.ac.kr (Lee SH), chanyshin@kku.ac.kr (Shin CY)
Tel: +82-2-820-5675 (Lee SH), +82-2-2030-7834 (Shin CY)
Fax: +82-2-816-7338 (Lee SH), +82-2-2049-6192 (Shin CY)
Received: February 20, 2020; Revised: March 19, 2020; Accepted: March 25, 2020; Published online: April 22, 2020.
© The Korean Society of Applied Pharmacology. All rights reserved.

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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