Commentary : a channelopathy mutation in the voltage-sensor discloses contributions of a conserved phenylalanine to gating properties of Kv1.1 channels and ataxia

Abstract

In a recent article, we reported a novel heterozygous mutation in the KCNA1 gene of a proband affected by episodic ataxia type 1 (EA1) (Hasan et al., 2017). The resulting substitution of a highly conserved phenylalanine in the Kv1.1 channel with a valine (p.F303V) led to positive shifts of voltage-dependence, altered kinetics of activation, deactivation and slow inactivation, reduced window currents, and decreased Kv1.1 current amplitude. Even with the critical location, within the voltage-sensing domain and amidst S4’s renowned arginine-lysine motif, it remains intriguing that the mutation causing debilitating symptoms and a remarkable impact on gating involves the neutral non-polar phenylalanine. In the open-state, the mobile S4 helix is stabilized by salt bridges formed between the charged residues that it contains and the acidic residues on S1 and S2 (Long et al., 2005). We constructed a model using rat Kv1.2 coordinates (Figure 1) that shows the open structure may further be stabilized by hydrophobic interactions. Substitution of the aromatic phenylalanine with the smaller aliphatic valine, as it appears in themutation, resulted in weaker hydrophobic interactions between S4’s F303V and both L339 and I335 of the S5 helix of a neighboring subunit. The mutation appears to reduce or abolish the effectiveness of these interactions, as well as that between side chains of F300 and F303 which lie in a stacked arrangement in the S4 helix, thereby destabilizing the channel’s open state.