The Journal of clinical investigation, 2015-10, Vol.125 (10), p.3904-3914
2015
Details
- Autor(en) / Beteiligte
- Titel
- M-current preservation contributes to anticonvulsant effects of valproic acid
- Ist Teil von
- The Journal of clinical investigation, 2015-10, Vol.125 (10), p.3904-3914
- Ort / Verlag
- United States: American Society for Clinical Investigation
- Erscheinungsjahr
- 2015
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0021-9738eISSN: 1558-8238DOI: 10.1172/JCI79727Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4607138
- Format
- –
- Schlagworte
- A Kinase Anchor Proteins - genetics, A Kinase Anchor Proteins - metabolism, A Kinase Anchor Proteins - physiology, Action Potentials - drug effects, Animals, Anthracenes - pharmacology, Anticonvulsants - pharmacology, Anticonvulsants - therapeutic use, Biomedical research, Bipolar disorder, Carbamates - pharmacology, Cells, Cultured, Divalproex, Dosage and administration, Drug Interactions, Epilepsy, Experiments, Female, Health aspects, Hippocampus - cytology, Humans, Kainic Acid - toxicity, KCNQ2 Potassium Channel - drug effects, KCNQ2 Potassium Channel - physiology, Kinases, Lipoylation - drug effects, Male, Mice, Mice, Inbred C57BL, Muscarinic Agonists - pharmacology, Muscarinic Antagonists - pharmacology, Neurons - drug effects, Neurons - metabolism, Pharmacology, Experimental, Phenylenediamines - pharmacology, Phosphorylation, Phosphorylation - drug effects, Potassium, Potassium Channel Blockers - pharmacology, Potassium channels, Preservation, Protein Processing, Post-Translational - drug effects, Rats, Receptor, Muscarinic M1 - drug effects, Receptor, Muscarinic M1 - physiology, Recombinant Fusion Proteins - drug effects, Recombinant Fusion Proteins - genetics, Recombinant Fusion Proteins - metabolism, Seizures - chemically induced, Seizures - drug therapy, Seizures - physiopathology, Signal Transduction - drug effects, Studies, Superior Cervical Ganglion - cytology, Valproic acid, Valproic Acid - pharmacology, Valproic Acid - therapeutic use