title: Mechanism of accelerated current decay caused by an episodic ataxia type-1-associated mutant in a potassium channel pore.
abstract: In Kv1.1, single point mutants found below the channel activation gate at residue V408 are associated with human episodic ataxia type-1, and impair channel function by accelerating decay of outward current during periods of membrane depolarization and channel opening. This decay is usually attributed to C-type inactivation, but here we provide evidence that this is not the case. Using voltage-clamp fluorimetry in Xenopus oocytes, and single-channel patch clamp in mouse ltk- cells, of the homologous Shaker channel (with the equivalent mutation V478A), we have determined that the mutation may cause current decay through a local effect at the activation gate, by destabilizing channel opening. We demonstrate that the effect of the mutant is similar to that of trapped 4-aminopyridine in antagonizing channel opening, as the mutation and 10 mm 4-AP had similar, nonadditive effects on fluorescence recorded from the voltage-sensitive S4 helix. We propose a model where the Kv1.1 activation gate fails to enter a stabilized open conformation, from which the channel would normally C-type inactivate. Instead, the lower pore lining helix is able to enter an activated-not-open conformation during depolarization. These results provide an understanding of the molecular etiology underlying episodic ataxia type-1 due to V408A, as well as biophysical insights into the links between the potassium channel activation gate, the voltage sensor and the selectivity filter.
authors: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors: Christian J
authors: CJ
authors: Peters
authors: Daniel
authors: D
authors: Werry
authors: Hira S
authors: HS
authors: Gill
authors: Eric A
authors: EA
authors: Accili
authors: David
authors: D
authors: Fedida
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000503:physiopathology; D015640:Ion Channel Gating / Q000235:genetics*; D051662:Kv1.1 Potassium Channel / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D014981:Xenopus; D029867:Xenopus Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D029867:Xenopus Proteins; C084069:kcna1 protein, Xenopus; D051662:Kv1.1 Potassium Channel; D011188:Potassium