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Protective Outcome of Attenuation of Kv7 Channel Suppression in the Pathology of Seizures and Epileptogenesis

Abstract

The M-current is a non-inactivating voltage-gated potassium channel composed of homomeric and heteromeric assemblies of KCNQ/Kv7 subunits (KCNQ2-5). The M-current exerts pronounced control over excitability during prolonged stimulus in neurons. The channel is transiently suppressed through pathways downstream of Gq-coupled receptor activation, allowing for enhanced signaling within neural circuits. However, several mutations in this channel have been implicated in epilepsies and encephalopathies. We sought to understand the functional relevance of M-current suppression in the pathology of epilepsy. First we needed a pharmacological tool to selectively partition M-current contribution in seizures. To this end we identified the mechanism of inhibition for XE991, a popular M-current inhibitor that until know lacked sufficient characterization. XE991 was determined to be an activated-subunit inhibitor with slow binding. By using this compound the M-current could be selectively suppressed in neurons contributing to ictal activities, as XE991 would be highly efficacious on rapidly depolarizing neurons, while having minimal effect on silent or sparsely firing neurons. Next, we identified an underlying mechanism for the widely used anticonvulsant, valproic acid. We determined that valproic acid acts as an inhibitor of palmitoylation, a posttranslational fatty acid modification. Specifically valproic acid prevented palmitoylation of a signaling scaffold protein within the Kv7 channel complex, AKAP79/150. As a result, valproic acid ablated M-current suppression from AKAP79/150-bound protein kinase C when stimulating Gq-coupled receptors, reducing neurotransmitter-induced hyperexcitability. In a kainate model of status epilepticus, the anticonvulsant action of valproic acid was transiently removed by M-current inhibition with XE991. Also, the M-current activator retigabine, which is not efficacious on neurotransmitter-suppressed channels, demonstrated anticonvulsive action even when administered after seizure induction if animals were pretreated with valproic acid. Using a transgenic mouse line carrying an alanine substitution of the key Kv7.2 phosphorylation site we confirmed that a dominant mechanism for the anticonvulsive action of valproic acid is through M-current preservation. Furthermore, prevention of M-current suppression after status epilepticus protected animals from the process of epileptogenesis. Our findings indicate that suppression of the M-current is involved in the pathology of epilepsy, and that interfering with channel suppression can robustly attenuate morbidities contributing to this neurological disorder.

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