A Structurally Precise Mechanism Links an Epilepsy-Associated KCNC2 Potassium Channel Mutation to Interneuron Dysfunction

Authors

Jerome Clatot
Christopher B. Currin
Qiansheng Liang, Thomas Jefferson UniversityFollow
Tanadet Pipatpolkai
Shavonne L. Massey
Ingo Helbig
Lucie Delemotte
Tim P. Vogels
Manuel Covarrubias
Ethan M. Goldberg

Document Type

Article

Publication Date

1-9-2024

Comments

This article is the author’s final published version in PNAS, Volume 121, Issue 3, January 2024, Article number e2307776121.

The published version is available at https://doi.org/10.1073/pnas.2307776121. Copyright © 2024 the Author(s). Published by PNAS.

Abstract

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.

Recommended Citation

Clatot, Jerome; Currin, Christopher B.; Liang, Qiansheng; Pipatpolkai, Tanadet; Massey, Shavonne L.; Helbig, Ingo; Delemotte, Lucie; Vogels, Tim P.; Covarrubias, Manuel; and Goldberg, Ethan M., "A Structurally Precise Mechanism Links an Epilepsy-Associated KCNC2 Potassium Channel Mutation to Interneuron Dysfunction" (2024). Farber Institute for Neuroscience Staff Papers and Presentations. Paper 5.
https://jdc.jefferson.edu/farberneurospapers/5

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Language

English