Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
A Disease Mutation Causing Episodic Ataxia Type I in the S1 Links Directly to the Voltage Sensor and the Selectivity Filter in Kv Channels.
Petitjean D
,
Kalstrup T
,
Zhao J
,
Blunck R
.
???displayArticle.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.
SIGNIFICANCE STATEMENT: 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 mechanism by which mutations in voltage-gated potassium channels lead to EA is still unknown and there is no consistent pharmacological treatment. By studying in detail one disease-causing mutation in Kv1.1, we describe a novel molecular mechanism distinct from mechanisms described previously. This mechanism contributes to the understanding of potassium channel function in general and might lead to a better understanding of how EA develops.
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
Alle,
Combined analog and action potential coding in hippocampal mossy fibers.
2006,
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
Berger,
The pore of the voltage-gated proton channel.
2011,
Pubmed
,
Xenbase
Bernèche,
A gate in the selectivity filter of potassium channels.
2005,
Pubmed
Bezanilla,
How membrane proteins sense voltage.
2008,
Pubmed
Bialowas,
Analog modulation of spike-evoked transmission in CA3 circuits is determined by axonal Kv1.1 channels in a time-dependent manner.
2015,
Pubmed
Blunck,
Mechanism of electromechanical coupling in voltage-gated potassium channels.
2012,
Pubmed
Bretschneider,
Expression in mammalian cells and electrophysiological characterization of two mutant Kv1.1 channels causing episodic ataxia type 1 (EA-1).
1999,
Pubmed
Browne,
Identification of two new KCNA1 mutations in episodic ataxia/myokymia families.
1995,
Pubmed
Chowdhury,
A self-consistent approach for determining pairwise interactions that underlie channel activation.
2014,
Pubmed
,
Xenbase
Claydon,
A direct demonstration of closed-state inactivation of K+ channels at low pH.
2007,
Pubmed
,
Xenbase
Cordero-Morales,
Molecular determinants of gating at the potassium-channel selectivity filter.
2006,
Pubmed
Cuello,
Structural mechanism of C-type inactivation in K(+) channels.
2010,
Pubmed
Cuello,
Structural basis for the coupling between activation and inactivation gates in K(+) channels.
2010,
Pubmed
Faure,
A limited 4 Å radial displacement of the S4-S5 linker is sufficient for internal gate closing in Kv channels.
2012,
Pubmed
Gagnon,
A single charged voltage sensor is capable of gating the Shaker K+ channel.
2009,
Pubmed
,
Xenbase
Geiger,
Dynamic control of presynaptic Ca(2+) inflow by fast-inactivating K(+) channels in hippocampal mossy fiber boutons.
2000,
Pubmed
Grosse,
Expression of Kv1 potassium channels in mouse hippocampal primary cultures: development and activity-dependent regulation.
2000,
Pubmed
Haddad,
Mode shift of the voltage sensors in Shaker K+ channels is caused by energetic coupling to the pore domain.
2011,
Pubmed
,
Xenbase
Hong,
The lipid-protein interface of a Shaker K(+) channel.
2000,
Pubmed
,
Xenbase
Horovitz,
Double-mutant cycles: a powerful tool for analyzing protein structure and function.
1996,
Pubmed
Jen,
Hereditary episodic ataxias.
2008,
Pubmed
Kalstrup,
Dynamics of internal pore opening in K(V) channels probed by a fluorescent unnatural amino acid.
2013,
Pubmed
,
Xenbase
Kole,
Axon initial segment Kv1 channels control axonal action potential waveform and synaptic efficacy.
2007,
Pubmed
Labro,
Kv channel gating requires a compatible S4-S5 linker and bottom part of S6, constrained by non-interacting residues.
2008,
Pubmed
Labro,
Molecular mechanism for depolarization-induced modulation of Kv channel closure.
2012,
Pubmed
,
Xenbase
Lacroix,
Tuning the voltage-sensor motion with a single residue.
2012,
Pubmed
Lacroix,
Moving gating charges through the gating pore in a Kv channel voltage sensor.
2014,
Pubmed
,
Xenbase
Lee,
Two separate interfaces between the voltage sensor and pore are required for the function of voltage-dependent K(+) channels.
2009,
Pubmed
,
Xenbase
Li-Smerin,
A localized interaction surface for voltage-sensing domains on the pore domain of a K+ channel.
2000,
Pubmed
,
Xenbase
Long,
Voltage sensor of Kv1.2: structural basis of electromechanical coupling.
2005,
Pubmed
Long,
Crystal structure of a mammalian voltage-dependent Shaker family K+ channel.
2005,
Pubmed
Long,
Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment.
2007,
Pubmed
Lu,
Ion conduction pore is conserved among potassium channels.
2001,
Pubmed
Lu,
Coupling between voltage sensors and activation gate in voltage-gated K+ channels.
2002,
Pubmed
,
Xenbase
Moran,
Level of expression controls modes of gating of a K+ channel.
1992,
Pubmed
,
Xenbase
Moreau,
Gating pore currents are defects in common with two Nav1.5 mutations in patients with mixed arrhythmias and dilated cardiomyopathy.
2015,
Pubmed
Olcese,
A conducting state with properties of a slow inactivated state in a shaker K(+) channel mutant.
2001,
Pubmed
,
Xenbase
Pathak,
The cooperative voltage sensor motion that gates a potassium channel.
2005,
Pubmed
,
Xenbase
Pathak,
Closing in on the resting state of the Shaker K(+) channel.
2007,
Pubmed
Perozo,
Gating currents from a nonconducting mutant reveal open-closed conformations in Shaker K+ channels.
1993,
Pubmed
Pongs,
Ancillary subunits associated with voltage-dependent K+ channels.
2010,
Pubmed
Ramsey,
A voltage-gated proton-selective channel lacking the pore domain.
2006,
Pubmed
Schoppa,
Activation of Shaker potassium channels. III. An activation gating model for wild-type and V2 mutant channels.
1998,
Pubmed
,
Xenbase
Shu,
Selective control of cortical axonal spikes by a slowly inactivating K+ current.
2007,
Pubmed
Sokolov,
Gating pore current in an inherited ion channelopathy.
2007,
Pubmed
,
Xenbase
Starace,
Histidine scanning mutagenesis of basic residues of the S4 segment of the shaker k+ channel.
2001,
Pubmed
,
Xenbase
Starace,
A proton pore in a potassium channel voltage sensor reveals a focused electric field.
2004,
Pubmed
Taglialatela,
Novel voltage clamp to record small, fast currents from ion channels expressed in Xenopus oocytes.
1992,
Pubmed
,
Xenbase
Tombola,
The twisted ion-permeation pathway of a resting voltage-sensing domain.
2007,
Pubmed
,
Xenbase
Tombola,
The voltage-gated proton channel Hv1 has two pores, each controlled by one voltage sensor.
2008,
Pubmed
,
Xenbase
Wall-Lacelle,
Double mutant cycle analysis identified a critical leucine residue in the IIS4S5 linker for the activation of the Ca(V)2.3 calcium channel.
2011,
Pubmed
Wang,
Localization of Kv1.1 and Kv1.2, two K channel proteins, to synaptic terminals, somata, and dendrites in the mouse brain.
1994,
Pubmed
Yang,
How does the W434F mutation block current in Shaker potassium channels?
1997,
Pubmed
,
Xenbase
Zagotta,
Shaker potassium channel gating. III: Evaluation of kinetic models for activation.
1994,
Pubmed
,
Xenbase
Zerr,
Episodic ataxia mutations in Kv1.1 alter potassium channel function by dominant negative effects or haploinsufficiency.
1998,
Pubmed
,
Xenbase
