Attenuating M-current suppression in vivo by a mutant Kcnq2 gene knock-in reduces seizure burden and prevents status epilepticus-induced neuronal death and epileptogenesis

Epilepsia
Derek L GreeneNaoto Hoshi

Abstract

The M-current is a low-threshold voltage-gated potassium current generated by Kv7 subunits that regulates neural excitation. It is important to note that M-current suppression, induced by activation of Gq-coupled neurotransmitter receptors, can dynamically regulate the threshold of action-potential firing and firing frequency. Here we sought to directly examine whether M-current suppression is involved in seizures and epileptogenesis. Kv7.2 knock-in mice lacking the key protein kinase C (PKC) phosphorylation acceptor site for M-current suppression were generated by introducing an alanine substitution at serine residue 559 of mouse Kv7.2, mKv7.2(S559A). Basic electrophysiologic properties of the M-current between wild-type and Kv7.2(S559A) knock-in mice were analyzed in primary cultured neurons. Homozygous Kv7.2(S559A) knock-in mice were used to evaluate the protective effect of mutant Kv7.2 channel against chemoconvulsant-induced seizures. In addition, pilocarpine-induced neuronal damage and spontaneously recurrent seizures were evaluated after equivalent chemoconvulsant-induced status epilepticus was achieved by coadministration of the M-current-specific channel inhibitor, XE991. Neurons from Kv7.2(S559A) knock-in mice showed ...Continue Reading

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Citations

Jun 9, 2020·Pflügers Archiv : European journal of physiology·Piera NappiMaurizio Taglialatela
Mar 24, 2021·Expert Opinion on Therapeutic Targets·E S Nikitin, L V Vinogradova
Jun 22, 2021·Frontiers in Molecular Neuroscience·Deepanjali Dwivedi, Upinder S Bhalla

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