A Common Kinetic Property of Mutations Linked to Episodic Ataxia Type 1 Studied in the Shaker Kv Channel

Juan Zhao,Georges A Haddad,Rikard Blunck,Dimitri Petitjean,Zarah Batulan

doi:10.3390/ijms21207602

Juan Zhao, Georges A Haddad + Show 3 more

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https://doi.org/10.3390/ijms21207602

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Abstract

(1) Background: Episodic ataxia type 1 is caused by mutations in the KCNA1 gene encoding for the voltage-gated potassium channel Kv1.1. There have been many mutations in Kv1.1 linked to episodic ataxia reported and typically investigated by themselves or in small groups. The aim of this article is to determine whether we can define a functional parameter common to all Kv1.1 mutants that have been linked to episodic ataxia. (2) Methods: We introduced the disease mutations linked to episodic ataxia in the drosophila analog of Kv1.1, the Shaker Kv channel, and expressed the channels in Xenopus oocytes. Using the cut-open oocyte technique, we characterized the gating and ionic currents. (3) Results: We found that the episodic ataxia mutations variably altered the different gating mechanisms described for Kv channels. The common characteristic was a conductance voltage relationship and inactivation shifted to less polarized potentials. (4) Conclusions: We suggest that a combination of a prolonged action potential and slowed and incomplete inactivation leads to development of ataxia when Kv channels cannot follow or adapt to high firing rates.

Highlights

IntroductionEpisodic ataxia type 1 (EA1) manifests itself as myokymia and episodes of cerebellar dysfunction with spastic contraction of skeletal muscles and loss of motor coordination, vertigo, migraine and ataxia
Episodic ataxia type 1 (EA1) is an autosomal dominant K+ channelopathy
We constructed a number of Kv1.1 mutants in the drosophila analog Kv1 Shaker channel (Table 1, numbering in this article according to Shaker). According to their position in the 3D structure, the mutants can be classified with few exceptions into two groups, those that are in the voltage sensor and those that are in the region of electromechanical coupling, i.e. the energetic coupling between the voltage sensor and the pore (Figure 1a,b)

Summary

Introduction

EA1 manifests itself as myokymia and episodes of cerebellar dysfunction with spastic contraction of skeletal muscles and loss of motor coordination, vertigo, migraine and ataxia. It is occasionally associated with epilepsy, dystonia, hemiplegic migraine, myasthenia and intermittent coma [1,2]. Kv1.1 (KCNA1) is expressed mainly in the axon and the distal axon initial segment but is found in the cell body and dendrites [3,4]. It may form heteromers with Kv1.2 and Kv1.4. As a member of the delayed outward rectifiers, the tetrameric Kv1.1 has the typical topology with six transmembrane helices S1–S6, where S1–S4 form four peripheral voltage sensors around a single central ion conducting pore domain formed by the four S5–S6 helices (Figure 1a,b)

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