Tracking the motion of the K_V1.2 voltage sensor reveals the molecular perturbations caused by a de novo mutation in a case of epilepsy.

ABSTRACT:

Key points

K_V1.2 channels, encoded by the KCNA2 gene, regulate neuronal excitability by conducting K⁺ upon depolarization. A new KCNA2 missense variant was discovered in a patient with epilepsy, causing amino acid substitution F302L at helix S4, in the K_V1.2 voltage-sensing domain. Immunocytochemistry and flow cytometry showed that F302L does not impair KCNA2 subunit surface trafficking. Molecular dynamics simulations indicated that F302L alters the exposure of S4 residues to membrane lipids. Voltage clamp fluorometry revealed that the voltage-sensing domain of K_V1.2-F302L channels is more sensitive to depolarization. Accordingly, K_V1.2-F302L channels opened faster and at more negative potentials; however, they also exhibited e

SUBMITTER: Pantazis A 

PROVIDER: S-EPMC8923147 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature