M-current preservation contributes to anticonvulsant effects of valproic acid

The Journal of Clinical Investigation
Hee Yeon KayNaoto Hoshi

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 in...Continue Reading

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Citations

Sep 21, 2016·Cellular and Molecular Life Sciences : CMLS·Derek L Greene, Naoto Hoshi
Dec 22, 2017·Epilepsia·Stephanie L Vanhoof-VillalbaEdward Glasscock
May 10, 2017·The Journal of Pharmacology and Experimental Therapeutics·Derek L GreeneNaoto Hoshi
Oct 16, 2018·Frontiers in Pharmacology·Jaya KumarSrijit Das
Dec 29, 2018·Current Neuropharmacology·Michele RomoliCinzia Costa
Apr 16, 2020·Frontiers in Synaptic Neuroscience·Alicia M Purkey, Mark L Dell'Acqua
Feb 28, 2016·Current Treatment Options in Neurology·Eric H GroverLawrence J Hirsch
Jun 4, 2019·Journal of Neurology·Zhi-Xu FangJin Chen
Dec 22, 2020·Clinical Science·Alessandra MurabitoAlessandra Ghigo

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Methods Mentioned

BETA
FRET
myristoylation
PCR
transfection
affinity purification

Software Mentioned

pClamp
MetaMorph

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