التفاصيل البيبلوغرافية
| العنوان: |
M-current preservation contributes to anticonvulsant effects of valproic acid |
| المؤلفون: |
Kay, Hee Yeon, Greene, Derek L, Kang, Seungwoo, Kosenko, Anastasia, Hoshi, Naoto |
| المصدر: |
Journal of Clinical Investigation, vol 125, iss 10 |
| بيانات النشر: |
eScholarship, University of California |
| سنة النشر: |
2015 |
| المجموعة: |
University of California: eScholarship |
| مصطلحات موضوعية: |
Neurosciences, Brain Disorders, Epilepsy, Neurodegenerative, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Neurological, A Kinase Anchor Proteins, Action Potentials, Animals, Anthracenes, Anticonvulsants, Carbamates, Cells, Cultured, Drug Interactions, Female, Hippocampus, Humans, KCNQ2 Potassium Channel, Kainic Acid, Lipoylation, Male, Mice, Inbred C57BL, Muscarinic Agonists, Muscarinic Antagonists, Neurons, Phenylenediamines, Phosphorylation |
| الوقت: |
3904 - 3914 |
| الوصف: |
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. |
| نوع الوثيقة: |
article in journal/newspaper |
| وصف الملف: |
application/pdf |
| اللغة: |
unknown |
| العلاقة: |
qt4zp1g153; https://escholarship.org/uc/item/4zp1g153Test |
| الإتاحة: |
https://escholarship.org/uc/item/4zp1g153Test |
| حقوق: |
public |
| رقم الانضمام: |
edsbas.62B3CB4B |
| قاعدة البيانات: |
BASE |
