RT Journal Article
SR Electronic
T1 Mechanism of Accelerated Current Decay Caused by an Episodic Ataxia Type-1-Associated Mutant in a Potassium Channel Pore
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 17449
OP 17459
DO 10.1523/JNEUROSCI.2940-11.2011
VO 31
IS 48
A1 Christian J. Peters
A1 Daniel Werry
A1 Hira S. Gill
A1 Eric A. Accili
A1 David Fedida
YR 2011
UL http://www.jneurosci.org/content/31/48/17449.abstract
AB 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.