title: Episodic ataxia/myokymia mutations functionally expressed in the Shaker potassium channel.
abstract: Episodic ataxia type 1 is a rare, autosomal dominant neurological disorder caused by missense mutations of the Kv1.1 gene from the Shaker K+ channel subfamily. To study the functional effects of the disease-causing mutations in a robust K+ channel background, we introduced seven different episodic ataxia type 1 substitutions into the corresponding, conserved residues of the Shaker K+ channel. K+ channel currents expressed in Xenopus oocytes were studied by electrophysiology. All episodic ataxia type 1 mutations produced functional K+ channels. In a Shaker N-terminal deletion mutant with fast inactivation removed, current amplitudes were significantly reduced in channels harboring an episodic ataxia type 1 mutation. Six of the seven mutations also showed depolarizing shifts (+9 to +36 mV) in the conductance voltage dependence. One mutation (F307I) shifted the midpoint of the conductance-voltage relationship by 23 mV in the hyperpolarizing direction. Episodic ataxia type 1 mutations were also expressed in ShakerH4 with intact N-terminal inactivation. In this construct, current amplitudes for episodic ataxia type 1 mutants were not significantly different from wild-type channels. All mutations altered the voltage range of steady-state inactivation; most changes were coupled to the changes in activation gating. Some episodic ataxia type 1 mutants also caused significant changes in the kinetics of N-type (F307I, E395D) or C-type (F307I, E395D, V478A) inactivation. These results suggest that episodic ataxia type 1 mutations may change K+ channel function by two mechanisms: (i) reduced channel expression and (ii) altered channel gating.
authors.affiliation: Department of Physiology, The University of Minnesota, Minneapolis, 55455, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Boland
authors.forename: D L
authors.initials: DL
authors.lastname: Price
authors.forename: K A
authors.initials: KA
authors.lastname: Jackson
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000503:physiopathology; D004330:Drosophila; D029721:Drosophila Proteins; D005207:Fasciculation / Q000235:genetics*; D005260:Female; D015640:Ion Channel Gating / Q000502:physiology; D009154:Mutation / Q000502:physiology*; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics*; D051637:Shaker Superfamily of Potassium Channels; D014982:Xenopus laevis
chemical_list: D029721:Drosophila Proteins; D015221:Potassium Channels; C496929:Sh protein, Drosophila; D051637:Shaker Superfamily of Potassium Channels