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M-current preservation contributes to anticonvulsant effects of valproic acid
Hee Yeon Kay, … , Anastasia Kosenko, Naoto Hoshi
Hee Yeon Kay, … , Anastasia Kosenko, Naoto Hoshi
Published September 8, 2015
Citation Information: J Clin Invest. 2015;125(10):3904-3914. https://doi.org/10.1172/JCI79727.
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Research Article Neuroscience Article has an altmetric score of 48

M-current preservation contributes to anticonvulsant effects of valproic acid

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Abstract

Valproic acid (VPA) has been widely used for decades to treat epilepsy; however, its mechanism of action remains poorly understood. Here, we report that the anticonvulsant effects of nonacute VPA treatment involve preservation of the M-current, a low-threshold noninactivating potassium current, during seizures. In a wide variety of neurons, activation of Gq-coupled receptors, such as the m1 muscarinic acetylcholine receptor, suppresses the M-current and induces hyperexcitability. We demonstrated that VPA treatment disrupts muscarinic suppression of the M-current and prevents resultant agonist-induced neuronal hyperexcitability. We also determined that VPA treatment interferes with M-channel signaling by inhibiting palmitoylation of a signaling scaffold protein, AKAP79/150, in cultured neurons. In a kainate-induced murine seizure model, administration of a dose of an M-channel inhibitor that did not affect kainate-induced seizure transiently eliminated the anticonvulsant effects of VPA. Retigabine, an M-channel opener that does not open receptor-suppressed M-channels, provided anticonvulsant effects only when administered prior to seizure induction in control animals. In contrast, treatment of VPA-treated mice with retigabine induced anticonvulsant effects even when administered after seizure induction. Together, these results suggest that receptor-induced M-current suppression plays a role in the pathophysiology of seizures and that preservation of the M-current during seizures has potential as an effective therapeutic strategy.

Authors

Hee Yeon Kay, Derek L. Greene, Seungwoo Kang, Anastasia Kosenko, Naoto Hoshi

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Figure 5

VPA disrupted PKC-mediated KCNQ2 regulation.

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VPA disrupted PKC-mediated KCNQ2 regulation.
(A) KCNQ2 current traces sh...
(A) KCNQ2 current traces showing that 500 μM VPA treatment attenuated 1 μM oxo-M induced current suppression in KCNQ2 channels. (B) Dose-response curve for VPA against oxo-M induced KCNQ2 current suppression. (C) Relative KCNQ2 currents 1 min after oxo-M application. Eighteen-hour treatment with 500 μM VPA reduced muscarinic suppression. Five-minute incubation with 500 μM VPA did not attenuate oxo-M response. KCNQ2S541A channels were more resistant to oxo-M. Notably, 18-hour treatment with 500 μM VPA had no effect. Amplitudes of currents are relative to those before oxo-M application. **P < 0.01 using Kruskal-Wallis one-way ANOVA followed by Dunn’s multiple comparisons test. Numbers on bars represent n values. (D) TIRF-FRET analysis between KCNQ2-mCit and CaM-mCer. Application of oxo-M decreased FRET signal corresponding to dissociation of CaM from KCNQ2 channel in control (open circle). VPA treatment prevented CaM dissociation (filled circle). Black box indicates presence of 3 μM oxo-M. (E) Oxo-M induced PKC activity measured by FRET-based PKC probe, cytCKAR. VPA did not have any effect. Black box indicates presence of 3 μM oxo-M. (F) PIP2 depletion measured by CFP-PH and EPI/TIRF microscope. Oxo-M (3 μM) induced translocation of CFP-PH. Fluorescent images are shown below for epi fluorescence (epi) and TIRF channel before (control) and after oxo-M (oxo) application. Scale bar: 10 μm. Error bars indicate ± SEM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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