Abstract
Voltage-gated potassium (Kv) channels are essential for setting neuronal membrane excitability. Mutations in human Kv1.1 channels are linked to episodic ataxia type 1 (EA1). The EA1-associated mutation I262T was identified from a patient with atypical phenotypes. Although a previous report has characterized its suppression effect, several key questions regarding the impact of the I262T mutation on Kv1.1 as well as other members of the Kv1 subfamily remain unanswered. Herein we show that the dominant-negative effect of I262T on Kv1.1 current expression is not reversed by co-expression with Kvβ1.1 or Kvβ2 subunits. Biochemical examinations indicate that I262T displays enhanced protein degradation and impedes membrane trafficking of Kv1.1 wild-type subunits. I262T appears to be the first EA1 mutation directly associated with impaired protein stability. Further functional analyses demonstrate that I262T changes the voltage-dependent activation and Kvβ1.1-mediated inactivation, uncouples inactivation from activation gating, and decelerates the kinetics of cumulative inactivation of Kv1.1 channels. I262T also exerts similar dominant effects on the gating of Kv1.2 and Kv1.4 channels. Together our data suggest that I262T confers altered channel gating and reduced functional expression of Kv1 channels, which may account for some of the phenotypes of the EA1 patient.
Highlights
A vast variety of different voltage-gated K+ (Kv) channels play critical roles in setting neuronal excitability, controlling neuronal firing frequencies, shaping action potential waveforms, and modulating neurotransmitter release[1,2]
The first question we asked was whether the Episodic ataxia type 1 (EA1)-associated mutation affects the voltage-dependent gating properties of Kv1.1 channels
We provide a series of different evidence showing that the EA1-assoicated I262T mutation may prominently modify the voltage-dependent gating properties of Kv1 channels
Summary
A vast variety of different voltage-gated K+ (Kv) channels play critical roles in setting neuronal excitability, controlling neuronal firing frequencies, shaping action potential waveforms, and modulating neurotransmitter release[1,2]. It is unknown whether I262T affects voltage-dependent activation and inactivation of Kv1.1 Nor is it clear how the mutation disrupts protein biosynthesis to manifest reduced surface expression of Kv1.1 channels. It remains to be determined regarding the effect of I262T on the gating of other isoforms of the Kv1 subfamily. To address these critical issues, we study the functional and biochemical properties of the I262T mutant in the absence or presence of different Kv1 α and Kvβ subunits. Our data suggest that the pathophysiological impact of the mutation entails both altered gating property and defective protein biosynthesis of Kv1.1 channels
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