Reduced axonal surface expression and phosphoinositide sensitivity in K_v7 channels disrupts their function to inhibit neuronal excitability in Kcnq2 epileptic encephalopathy.

ABSTRACT: Neuronal K_v7/KCNQ channels are voltage-gated potassium channels composed of K_v7.2/KCNQ2 and K_v7.3/KCNQ3 subunits. Enriched at the axonal membrane, they potently suppress neuronal excitability. De novo and inherited dominant mutations in K_v7.2 cause early onset epileptic encephalopathy characterized by drug resistant seizures and profound psychomotor delay. However, their precise pathogenic mechanisms remain elusive. Here, we investigated selected epileptic encephalopathy causing mutations in calmodulin (CaM)-binding helices A and B of K_v7.2. We discovered that R333W, K526N, and R532W mutations located peripheral to CaM contact sites decreased axonal surface expression of heteromeric channels although only R333W mutation reduced CaM bin

SUBMITTER: Kim EC 

PROVIDER: S-EPMC6415549 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature