A Disease Mutation Causing Episodic Ataxia Type I in the S1 Links Directly to the Voltage Sensor and the Selectivity Filter in Kv Channels

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Dimitri PetitjeanRikard Blunck

Abstract

The mutation F184C in Kv1.1 leads to development of episodic ataxia type I (EA1). Although the mutation has been said to alter activation kinetics and to lower expression, we show here that the underlying molecular mechanisms may be more complex. Although F184 is positioned in the "peripheral" S1 helix, it occupies a central position in the 3D fold. We show in cut-open oocyte voltage-clamp recordings of gating and ionic currents of the Shaker Kv channel expressed in Xenopus oocytes that F184 not only interacts directly with the gating charges of the S4, but also creates a functional link to the selectivity filter of the neighboring subunit. This link leads to impaired fast and slow inactivation. The effect on fast inactivation is of an allosteric nature considering that fast inactivation is caused by a linked cytosolic ball peptide. The extensive effects of F184C provide a new mechanism underlying EA. Episodic ataxia (EA) is an inherited disease that leads to occasional loss of motor control in combination with variable other symptoms such as vertigo or migraine. EA type I (EA1), studied here, is caused by mutations in a voltage-gated potassium channel that contributes to the generation of electrical signals in the brain. The m...Continue Reading

Citations

Apr 23, 2020·International Journal of Molecular Sciences·Kelsey PaulhusEdward Glasscock
Feb 22, 2017·Scientific Reports·Elizabeth A Ferrick-KiddieRonald B Emeson
Apr 26, 2020·International Journal of Molecular Sciences·Maria Cristina D'AdamoPaola Imbrici
Oct 18, 2020·International Journal of Molecular Sciences·Juan ZhaoRikard Blunck

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