M-current preservation contributes to anticonvulsant effects of valproic acid.
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.
Hee Yeon
HY
Kay
Derek L
DL
Greene
Seungwoo
S
Kang
Anastasia
A
Kosenko
Naoto
N
Hoshi
D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D002219:Carbamates / Q000494:pharmacology; D002478:Cells, Cultured; D004347:Drug Interactions; D005260:Female; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D051658:KCNQ2 Potassium Channel / Q000187:drug effects / Q000502:physiology*; D007608:Kainic Acid / Q000633:toxicity; D054878:Lipoylation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010655:Phenylenediamines / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000187:drug effects / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D017783:Superior Cervical Ganglion / Q000166:cytology; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use
C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D054758:A Kinase Anchor Proteins; C487775:AKAP5 protein, human; C415703:Akap5 protein, rat; D000873:Anthracenes; D000927:Anticonvulsants; D002219:Carbamates; D051658:KCNQ2 Potassium Channel; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D010655:Phenylenediamines; D026902:Potassium Channel Blockers; D043643:Receptor, Muscarinic M1; D011993:Recombinant Fusion Proteins; C101866:ezogabine; D014635:Valproic Acid; D007608:Kainic Acid