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Valproic acid inhibits ATP‐triggered Ca 2+ release via a p38‐dependent mechanism in bEND.3 endothelial cells
Author(s) -
Leong IatLon,
Tsai TienYao,
Wong KarLok,
Shiao LianRu,
Cheng KaShun,
Chan Paul,
Leung YukMan
Publication year - 2018
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/fcp.12381
Subject(s) - cyclopiazonic acid , phospholipase c , chemistry , microbiology and biotechnology , signal transduction , thapsigargin , pharmacology , intracellular , biology , biochemistry
Valproic acid (VA) is currently used to treat epilepsy and bipolar disorder. It has also been demonstrated to promote neuroprotection and neurogenesis. Although beneficial actions of VA on brain blood vessels have also been demonstrated, the effects of VA on brain endothelial cell (EC) Ca 2+ signaling are hitherto unreported. In this report, we examined the effects of VA on agonist‐triggered Ca 2+ signaling in mouse cortical bEND.3 EC. While VA (100 μ m ) did not cause an acute inhibition of ATP‐triggered Ca 2+ signaling, a 30‐min VA treatment strongly suppressed ATP‐triggered intracellular Ca 2+ release; however, such treatment did not affect Ca 2+ release triggered by cyclopiazonic acid, an inhibitor of SERCA Ca 2+ pump, suggesting there was no reduction in Ca 2+ store size. VA‐activated p38 signaling, and VA‐induced inhibition of ATP‐triggered Ca 2+ release was prevented by SB203580, a p38 inhibitor, suggesting VA caused the inhibition by activating p38. Remarkably, VA treatment did not affect acetylcholine‐triggered Ca 2+ release, suggesting VA may not inhibit inositol 1,4,5‐trisphosphate‐induced Ca 2+ release per se , and may not act directly on Gq or phospholipase C. Taken together, our results suggest VA treatment, via a p38‐dependent mechanism, led to an inhibition of purinergic receptor‐effector coupling.