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Proc Natl Acad Sci U S A
2018 Apr 10;11515:E3559-E3568. doi: 10.1073/pnas.1717082115.
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Kv4.2 autism and epilepsy mutation enhances inactivation of closed channels but impairs access to inactivated state after opening.
Lin MA, Cannon SC, Papazian DM.
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A de novo mutation in the KCND2 gene, which encodes the Kv4.2 K+ channel, was identified in twin boys with intractable, infant-onset epilepsy and autism. Kv4.2 channels undergo closed-state inactivation (CSI), a mechanism by which channels inactivate without opening during subthreshold depolarizations. CSI dynamically modulates neuronal excitability and action potential back propagation in response to excitatory synaptic input, controlling Ca2+ influx into dendrites and regulating spike timing-dependent plasticity. Here, we show that the V404M mutation specifically affects the mechanism of CSI, enhancing the inactivation of channels that have not opened while dramatically impairing the inactivation of channels that have opened. The mutation gives rise to these opposing effects by increasing the stability of the inactivated state and in parallel, profoundly slowing the closure of open channels, which according to our data, is required for CSI. The larger volume of methionine compared with valine is a major factor underlying altered inactivation gating. Our results suggest that V404M increases the strength of the physical interaction between the pore gate and the voltage sensor regardless of whether the gate is open or closed. Furthermore, in contrast to previous proposals, our data strongly suggest that physical coupling between the voltage sensor and the pore gate is maintained in the inactivated state. The state-dependent effects of V404M on CSI are expected to disturb the regulation of neuronal excitability and the induction of spike timing-dependent plasticity. Our results strongly support a role for altered CSI gating in the etiology of epilepsy and autism in the affected twins.
Aggarwal,
Contribution of the S4 segment to gating charge in the Shaker K+ channel.
1996, Pubmed,
Xenbase
Aggarwal,
Contribution of the S4 segment to gating charge in the Shaker K+ channel.
1996,
Pubmed
,
Xenbase Akemann,
Interaction of Kv3 potassium channels and resurgent sodium current influences the rate of spontaneous firing of Purkinje neurons.
2006,
Pubmed Amarillo,
Ternary Kv4.2 channels recapitulate voltage-dependent inactivation kinetics of A-type K+ channels in cerebellar granule neurons.
2008,
Pubmed An,
Modulation of A-type potassium channels by a family of calcium sensors.
2000,
Pubmed
,
Xenbase Bähring,
Voltage sensor inactivation in potassium channels.
2012,
Pubmed Bähring,
Mechanisms of closed-state inactivation in voltage-gated ion channels.
2011,
Pubmed Barghaan,
Dynamic coupling of voltage sensor and gate involved in closed-state inactivation of kv4.2 channels.
2009,
Pubmed
,
Xenbase Beck,
Remodelling inactivation gating of Kv4 channels by KChIP1, a small-molecular-weight calcium-binding protein.
2002,
Pubmed
,
Xenbase Cai,
Unique roles of SK and Kv4.2 potassium channels in dendritic integration.
2004,
Pubmed Chen,
Deletion of Kv4.2 gene eliminates dendritic A-type K+ current and enhances induction of long-term potentiation in hippocampal CA1 pyramidal neurons.
2006,
Pubmed Covarrubias,
The neuronal Kv4 channel complex.
2008,
Pubmed Dougherty,
Gating charge immobilization in Kv4.2 channels: the basis of closed-state inactivation.
2008,
Pubmed Duarri,
Functional analysis helps to define KCNC3 mutational spectrum in Dutch ataxia cases.
2015,
Pubmed Espinosa,
Alcohol hypersensitivity, increased locomotion, and spontaneous myoclonus in mice lacking the potassium channels Kv3.1 and Kv3.3.
2001,
Pubmed Fineberg,
Closed-state inactivation involving an internal gate in Kv4.1 channels modulates pore blockade by intracellular quaternary ammonium ions.
2016,
Pubmed
,
Xenbase Fineberg,
Modeling-independent elucidation of inactivation pathways in recombinant and native A-type Kv channels.
2012,
Pubmed
,
Xenbase Guo,
Targeted deletion of Kv4.2 eliminates I(to,f) and results in electrical and molecular remodeling, with no evidence of ventricular hypertrophy or myocardial dysfunction.
2005,
Pubmed Haddad,
Mode shift of the voltage sensors in Shaker K+ channels is caused by energetic coupling to the pore domain.
2011,
Pubmed
,
Xenbase Harpaz,
Volume changes on protein folding.
1994,
Pubmed Heler,
Homology model and targeted mutagenesis identify critical residues for arachidonic acid inhibition of Kv4 channels.
2013,
Pubmed
,
Xenbase Hoffman,
K+ channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons.
1997,
Pubmed Holmgren,
The activation gate of a voltage-gated K+ channel can be trapped in the open state by an intersubunit metal bridge.
1998,
Pubmed Hoshi,
Biophysical and molecular mechanisms of Shaker potassium channel inactivation.
1990,
Pubmed
,
Xenbase Jerng,
Modulation of Kv4.2 channel expression and gating by dipeptidyl peptidase 10 (DPP10).
2004,
Pubmed
,
Xenbase Jerng,
Molecular physiology and modulation of somatodendritic A-type potassium channels.
2004,
Pubmed Jerng,
Inactivation gating of Kv4 potassium channels: molecular interactions involving the inner vestibule of the pore.
1999,
Pubmed
,
Xenbase Jerng,
Multiprotein assembly of Kv4.2, KChIP3 and DPP10 produces ternary channel complexes with ISA-like properties.
2005,
Pubmed
,
Xenbase Jerng,
Modulatory mechanisms and multiple functions of somatodendritic A-type K (+) channel auxiliary subunits.
2014,
Pubmed Johnston,
Dendritic potassium channels in hippocampal pyramidal neurons.
2000,
Pubmed Kim,
Kv4 potassium channel subunits control action potential repolarization and frequency-dependent broadening in rat hippocampal CA1 pyramidal neurones.
2005,
Pubmed Kiss,
Modulation of C-type inactivation by K+ at the potassium channel selectivity filter.
1998,
Pubmed Labro,
Molecular mechanism for depolarization-induced modulation of Kv channel closure.
2012,
Pubmed
,
Xenbase Labro,
Kv3.1 uses a timely resurgent K(+) current to secure action potential repolarization.
2015,
Pubmed
,
Xenbase Lee,
Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation.
2014,
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,
Coupling between voltage sensors and activation gate in voltage-gated K+ channels.
2002,
Pubmed
,
Xenbase Martina,
Properties and functional role of voltage-dependent potassium channels in dendrites of rat cerebellar Purkinje neurons.
2003,
Pubmed Matsukawa,
Motor dysfunction and altered synaptic transmission at the parallel fiber-Purkinje cell synapse in mice lacking potassium channels Kv3.1 and Kv3.3.
2003,
Pubmed Menegola,
Unanticipated region- and cell-specific downregulation of individual KChIP auxiliary subunit isotypes in Kv4.2 knock-out mouse brain.
2006,
Pubmed Migliore,
Role of an A-type K+ conductance in the back-propagation of action potentials in the dendrites of hippocampal pyramidal neurons.
1999,
Pubmed Minassian,
Altered Kv3.3 channel gating in early-onset spinocerebellar ataxia type 13.
2012,
Pubmed
,
Xenbase Nerbonne,
Molecular physiology of cardiac repolarization.
2005,
Pubmed Olcese,
A conducting state with properties of a slow inactivated state in a shaker K(+) channel mutant.
2001,
Pubmed
,
Xenbase Oxford,
Some kinetic and steady-state properties of sodium channels after removal of inactivation.
1981,
Pubmed Papazian,
Alteration of voltage-dependence of Shaker potassium channel by mutations in the S4 sequence.
1991,
Pubmed
,
Xenbase Pau,
Crystal structure of an inactivated mutant mammalian voltage-gated K+ channel.
2017,
Pubmed Pioletti,
Three-dimensional structure of the KChIP1-Kv4.3 T1 complex reveals a cross-shaped octamer.
2006,
Pubmed
,
Xenbase Piper,
Gating currents associated with intramembrane charge displacement in HERG potassium channels.
2003,
Pubmed
,
Xenbase Ramakers,
A postsynaptic transient K(+) current modulated by arachidonic acid regulates synaptic integration and threshold for LTP induction in hippocampal pyramidal cells.
2002,
Pubmed Rhodes,
KChIPs and Kv4 alpha subunits as integral components of A-type potassium channels in mammalian brain.
2004,
Pubmed Rudy,
Kv3 channels: voltage-gated K+ channels designed for high-frequency repetitive firing.
2001,
Pubmed Santiago-Castillo,
Simulating complex ion channel kinetics with IonChannelLab.
2010,
Pubmed Seoh,
Voltage-sensing residues in the S2 and S4 segments of the Shaker K+ channel.
1996,
Pubmed
,
Xenbase Serôdio,
Cloning of a novel component of A-type K+ channels operating at subthreshold potentials with unique expression in heart and brain.
1996,
Pubmed
,
Xenbase Serôdio,
Differential expression of Kv4 K+ channel subunits mediating subthreshold transient K+ (A-type) currents in rat brain.
1998,
Pubmed Timpe,
Expression of functional potassium channels from Shaker cDNA in Xenopus oocytes.
1988,
Pubmed
,
Xenbase Truchet,
Kv4 potassium channels modulate hippocampal EPSP-spike potentiation and spatial memory in rats.
2012,
Pubmed Villalba-Galea,
S4-based voltage sensors have three major conformations.
2008,
Pubmed Wang,
Structural basis for modulation of Kv4 K+ channels by auxiliary KChIP subunits.
2007,
Pubmed
,
Xenbase Watanabe,
Dendritic K+ channels contribute to spike-timing dependent long-term potentiation in hippocampal pyramidal neurons.
2002,
Pubmed Waters,
Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes.
2006,
Pubmed
,
Xenbase Webster,
Intracellular gate opening in Shaker K+ channels defined by high-affinity metal bridges.
2004,
Pubmed Wollberg,
Intra- and Intersubunit Dynamic Binding in Kv4.2 Channel Closed-State Inactivation.
2016,
Pubmed
,
Xenbase Yifrach,
Energetics of pore opening in a voltage-gated K(+) channel.
2002,
Pubmed
,
Xenbase Zagotta,
Restoration of inactivation in mutants of Shaker potassium channels by a peptide derived from ShB.
1990,
Pubmed
,
Xenbase Zagotta,
Shaker potassium channel gating. III: Evaluation of kinetic models for activation.
1994,
Pubmed
,
Xenbase
