A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction

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QC 20240125
De novo heterozygous variants in KCNC2 encoding the voltage-gated potassium (K+) channel subunit Kv3.2 are a recently described cause of developmental and epileptic encephalopathy (DEE). A de novo variant in KCNC2 c.374G > A (p.Cys125Tyr) was identified via exome sequencing in a patient with DEE. Relative to wild-type Kv3.2, Kv3.2-p.Cys125Tyr induces K+ currents exhibiting a large hyperpolarizing shift in the voltage dependence of activation, accelerated activation, and delayed deactivation consistent with a relative stabilization of the open conformation, along with increased current density. Leveraging the cryogenic electron microscopy (cryo-EM) structure of Kv3.1, molecular dynamic simulations suggest that a strong π-π stacking interaction between the variant Tyr125 and Tyr156 in the α-6 helix of the T1 domain promotes a relative stabilization of the open conformation of the channel, which underlies the observed gain of function. A multicompartment computational model of a Kv3-expressing parvalbumin-positive cerebral cortex fast-spiking γ-aminobutyric acidergic (GABAergic) interneuron (PV-IN) demonstrates how the Kv3.2-Cys125Tyr variant impairs neuronal excitability and dysregulates inhibition in cerebral cortex circuits to explain the resulting epilepsy.

Currin, Christopher B. (author)
Liang, Qiansheng (author)
Pipatpolkai, TanadetKTH,Biofysik,Science for Life Laboratory, SciLifeLab(Swepub:kth)u1i8emky (author)
Massey, Shavonne L. (author)
Helbig, Ingo (author)
Delemotte, LucieKTH,Biofysik,Science for Life Laboratory, SciLifeLab(Swepub:kth)u15w0he7 (author)
Vogels, Tim P. (author)
Covarrubias, Manuel (author)
Goldberg, Ethan M. (author)
KTHBiofysik (creator_code:org_t)

In:Proceedings of the National Academy of Sciences of the United States of America: Proceedings of the National Academy of Sciences121:30027-84241091-6490

By the author/editor: Clatot, Jerome; Currin, Christop ...; Liang, Qiansheng; Pipatpolkai, Tan ...; Massey, Shavonne ...; Helbig, Ingo; show more...; Delemotte, Lucie; Vogels, Tim P.; Covarrubias, Man ...; Goldberg, Ethan ...; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

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