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J Neurosci
2011 Nov 30;3148:17449-59. doi: 10.1523/JNEUROSCI.2940-11.2011.
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Mechanism of accelerated current decay caused by an episodic ataxia type-1-associated mutant in a potassium channel pore.
Peters CJ
,
Werry D
,
Gill HS
,
Accili EA
,
Fedida D
.
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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.
Adelman,
Episodic ataxia results from voltage-dependent potassium channels with altered functions.
1995, Pubmed,
Xenbase
Adelman,
Episodic ataxia results from voltage-dependent potassium channels with altered functions.
1995,
Pubmed
,
Xenbase
Armstrong,
A model for 4-aminopyridine action on K channels: similarities to tetraethylammonium ion action.
2001,
Pubmed
Batulan,
An intersubunit interaction between S4-S5 linker and S6 is responsible for the slow off-gating component in Shaker K+ channels.
2010,
Pubmed
Baukrowitz,
Modulation of K+ current by frequency and external [K+]: a tale of two inactivation mechanisms.
1995,
Pubmed
Bezanilla,
The voltage sensor in voltage-dependent ion channels.
2000,
Pubmed
Browne,
Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1.
1994,
Pubmed
Cha,
Characterizing voltage-dependent conformational changes in the Shaker K+ channel with fluorescence.
1997,
Pubmed
,
Xenbase
Claydon,
4-aminopyridine prevents the conformational changes associated with p/c-type inactivation in shaker channels.
2007,
Pubmed
,
Xenbase
Colquhoun,
Fast events in single-channel currents activated by acetylcholine and its analogues at the frog muscle end-plate.
1985,
Pubmed
D'Adamo,
Mutations in the KCNA1 gene associated with episodic ataxia type-1 syndrome impair heteromeric voltage-gated K(+) channel function.
1999,
Pubmed
,
Xenbase
D'Adamo,
Episodic ataxia type-1 mutations in the hKv1.1 cytoplasmic pore region alter the gating properties of the channel.
1998,
Pubmed
,
Xenbase
Demo,
The inactivation gate of the Shaker K+ channel behaves like an open-channel blocker.
1991,
Pubmed
Demos,
A novel KCNA1 mutation associated with global delay and persistent cerebellar dysfunction.
2009,
Pubmed
Dougherty,
Gating charge immobilization in Kv4.2 channels: the basis of closed-state inactivation.
2008,
Pubmed
Doyle,
The structure of the potassium channel: molecular basis of K+ conduction and selectivity.
1998,
Pubmed
Fedida,
Slow gating charge immobilization in the human potassium channel Kv1.5 and its prevention by 4-aminopyridine.
1996,
Pubmed
Hackos,
Scanning the intracellular S6 activation gate in the shaker K+ channel.
2002,
Pubmed
,
Xenbase
Haddad,
Mode shift of the voltage sensors in Shaker K+ channels is caused by energetic coupling to the pore domain.
2011,
Pubmed
,
Xenbase
Herson,
A mouse model of episodic ataxia type-1.
2003,
Pubmed
Hoshi,
Biophysical and molecular mechanisms of Shaker potassium channel inactivation.
1990,
Pubmed
,
Xenbase
Imbrici,
Episodic ataxia type 1 mutations in the KCNA1 gene impair the fast inactivation properties of the human potassium channels Kv1.4-1.1/Kvbeta1.1 and Kv1.4-1.1/Kvbeta1.2.
2006,
Pubmed
,
Xenbase
Kitaguchi,
Stabilizing the closed S6 gate in the Shaker Kv channel through modification of a hydrophobic seal.
2004,
Pubmed
,
Xenbase
Lacroix,
Properties of deactivation gating currents in Shaker channels.
2011,
Pubmed
Ledwell,
Mutations in the S4 region isolate the final voltage-dependent cooperative step in potassium channel activation.
1999,
Pubmed
,
Xenbase
Levy,
Recovery from C-type inactivation is modulated by extracellular potassium.
1996,
Pubmed
Liu,
Gated access to the pore of a voltage-dependent K+ channel.
1997,
Pubmed
Long,
Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment.
2007,
Pubmed
Loots,
Molecular coupling of S4 to a K(+) channel's slow inactivation gate.
2000,
Pubmed
Loots,
Protein rearrangements underlying slow inactivation of the Shaker K+ channel.
1998,
Pubmed
Lu,
Coupling between voltage sensors and activation gate in voltage-gated K+ channels.
2002,
Pubmed
,
Xenbase
López-Barneo,
Effects of external cations and mutations in the pore region on C-type inactivation of Shaker potassium channels.
1993,
Pubmed
,
Xenbase
Mannuzzu,
Direct physical measure of conformational rearrangement underlying potassium channel gating.
1996,
Pubmed
,
Xenbase
Marom,
State-dependent inactivation of the Kv3 potassium channel.
1994,
Pubmed
,
Xenbase
Maylie,
Episodic ataxia type 1 mutations in the human Kv1.1 potassium channel alter hKvbeta 1-induced N-type inactivation.
2002,
Pubmed
,
Xenbase
McCormack,
A characterization of the activating structural rearrangements in voltage-dependent Shaker K+ channels.
1994,
Pubmed
Olcese,
Correlation between charge movement and ionic current during slow inactivation in Shaker K+ channels.
1997,
Pubmed
,
Xenbase
Shin,
Inactivation in HCN channels results from reclosure of the activation gate: desensitization to voltage.
2004,
Pubmed
Sigworth,
Data transformations for improved display and fitting of single-channel dwell time histograms.
1987,
Pubmed
Smith-Maxwell,
Role of the S4 in cooperativity of voltage-dependent potassium channel activation.
1998,
Pubmed
,
Xenbase
Soler-Llavina,
Functional interactions at the interface between voltage-sensing and pore domains in the Shaker K(v) channel.
2006,
Pubmed
,
Xenbase
Sørensen,
Deletion of the S3-S4 linker in the Shaker potassium channel reveals two quenching groups near the outside of S4.
2000,
Pubmed
,
Xenbase
VanDyke,
Hereditary myokymia and periodic ataxia.
1975,
Pubmed
Villalba-Galea,
S4-based voltage sensors have three major conformations.
2008,
Pubmed
Yifrach,
Energetics of pore opening in a voltage-gated K(+) channel.
2002,
Pubmed
,
Xenbase
Zhou,
Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors.
2001,
Pubmed
,
Xenbase
Zhou,
Chemistry of ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0 A resolution.
2001,
Pubmed
del Camino,
Status of the intracellular gate in the activated-not-open state of shaker K+ channels.
2005,
Pubmed
,
Xenbase