Figure 9. A working model for pathogenic mechanisms of epileptic encephalopathy mutations in helices A and B of K_v7.2.

Epileptic encephalopathy mutations (R333W, K526N, and R532W) localized peripheral to CaM contact sites in helices A and B reduced axonal surface expression of K_v7 channels, altered their sensitivity to PIP₂, and disrupted their ability to inhibit excitability in hippocampal neurons. In contrast, M518V mutation at the CaM contact site in helix B severely decreased CaM binding, axonal surface expression, and voltage-dependent activation. Intracellular accumulation of K_v7.2-M518V also caused cell death. We propose that a combination of these multiple yet diverse defects in K_v7 channels could exert more severe impacts on neuronal excitability and health, and thus serve as pathogenic mechanisms underlying Kcnq2 epileptic encephalopathy.