{Reference Type}: Journal Article
{Title}: A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction.
{Author}: Clatot J;Currin CB;Liang Q;Pipatpolkai T;Massey SL;Helbig I;Delemotte L;Vogels TP;Covarrubias M;Goldberg EM;
{Journal}: Proc Natl Acad Sci U S A
{Volume}: 121
{Issue}: 3
{Year}: 2024 Jan 16
{Factor}: 12.779
{DOI}: 10.1073/pnas.2307776121
{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.