<span lang="EN-US">Valproic Acid Stimulates Release of Ca²<span lang="EN-US">⁺<span lang="EN-US"> from InsP<span lang="EN-US">₃<span lang="EN-US">-Sensitive Ca<span lang="EN-US">²<span lang="EN-US">⁺<span lang="EN-US"> Stores

Calcium signaling dysfunction is a central contributor to neuronal hyperexcitability and seizure propagation in epilepsy, yet the intracellular mechanisms underlying the actions of valproic acid (VPA) remain incompletely un-derstood. In this study, we investigated whether VPA modulates calcium homeostasis at the level of the endo-plasmic reticulum (ER) and how this action influences cytosolic calcium dynamics associated with epileptiform activity. ER calcium levels were directly measured using ER-targeted aequorin in HeLa and PC12 cells, while cy-tosolic Ca²⁺ signals were monitored by fura-2 fluorescence imaging in bovine chromaffin cells exposed to veratri-dine, a model of sustained sodium channel activation and calcium oscillations. VPA induced a concentra-tion-dependent release of Ca²⁺ from the ER, with an IC₅₀ of approximately 17 µM. This effect was preserved in permeabilized cells and exhibited activation kinetics comparable to those elicited by inositol 1,4,5-trisphosphate (InsP₃). Pharmacological inhibition of InsP₃ receptors (InsP₃Rs), but not ryanodine receptors or SERCA, abolished VPA-induced ER Ca²⁺ release, supporting a selective InsP₃R-mediated mechanism. Functionally, VPA suppressed the repetitive cytosolic Ca²⁺ oscillations induced by veratridine, while simultaneously producing a sustained ele-vation of cytosolic Ca²⁺ originating from ER stores and facilitating depolarization-evoked catecholamine secretion. Together, these results support the conclusion that VPA acts as a novel functional agonist of InsP₃Rs and identify ER Ca²⁺ mobilization as a previously unrecognized intracellular mechanism contributing to its modulatory effects on calcium signaling and excitability in epilepsy.