Modeling-independent elucidation of inactivation pathways in recombinant and native A-type Kv channels

Fineberg, Jeffrey D.; Ritter, D. M.; Covarrubias, Manuel

doi:10.1085/jgp.201210869

Cited by 24 publications

(35 citation statements)

References 53 publications

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“…As the open probability increased at more positive voltages, however, CSI was progressively slower. Similar results have been reported previously, providing evidence that Kv4.2 channels preferentially inactivate from preopen closed states (24)(25)(26)37). According to this proposal, inactivation is slower after opening, because open channels must close before inactivating.…”

Section: Resultssupporting

confidence: 89%

“…The finding that slow pore closing is correlated with dramatically impaired inactivation strongly supports the conclusion that open Kv4.2 channels must close to inactivate by the CSI mechanism (26). Indeed, closing is required if the pore gate is responsible for occluding ion flow in the inactivated state, a proposal that is highly consistent with our data (22,(24)(25)(26).…”

Section: Increase In Side-chain Volume Contributes Substantially To Fsupporting

confidence: 90%

“…As a result, inactivation directly from preopen closed states is enhanced in mutant channels compared with wild-type Kv4.2. However, inactivation is severely impaired after the channel opens, because V404M dramatically slows the rate of pore closure, consistent with evidence that open Kv4.2 channels must close to inactivate (24)(25)(26). We also find that the increase in side-chain volume that occurs in the valine-to-methionine mutation plays a key role in the kinetic changes in gating seen in V404M channels.…”

supporting

confidence: 83%

“…In contrast, CSI in Kv4 channels is coupled to voltage sensor conformational changes evoked by depolarization rather than to pore opening (5,10,24). From partially or fully activated closed states, the voltage sensor can enter an alternative conformation, C ‡ , in which the bundle-crossing gate becomes reluctant to open (Fig.…”

mentioning

confidence: 99%

“…Evidence suggests that the bundle-crossing gate is responsible for occluding the pore in the inactivated conformation. Accordingly, open channels would need to close to inactivate (22,24,25).…”

mentioning

confidence: 99%

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Kv4.2 autism and epilepsy mutation enhances inactivation of closed channels but impairs access to inactivated state after opening

Lin

Cannon

Papazian

2018

Proc. Natl. Acad. Sci. U.S.A.

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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, infantonset 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 Ca 2+ 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.ecently, a de novo mutation in the KCND2 gene was identified by exome sequencing in monozygotic twin boys with intractable seizures starting in infancy, autism, and intellectual disability (1). KCND2 encodes the Kv4.2 voltage-gated K + channel. Kv4.2 and other members of the Kv4 family serve as the pore-forming subunits in inactivating, somatodendritic A-type K + (I SA ) channels, which are widely expressed in the brain (2-8). Kv4.2 is the sole pore-forming subunit in I SA channels found in pyramidal cells in the CA1 region of the hippocampus (6, 7). The hallmark property of I SA channels is the ability to inactivate without opening during subthreshold excitatory postsynaptic potentials (5,8,9). This occurs through the mechanism of closedstate inactivation (CSI) (5, 10). CSI determines the steady-state availability of I SA channels and thereby controls resting excitability and firing frequency (5,8,9). In addition, CSI temporarily increases excitability in response to excitatory synaptic input, boosting the back propagation of action potentials and Ca 2+ influx into dendrites (7,(11)(12)(13)(14)(15)(16)(17). As a result, CSI is a key component in mechanisms of spike timing-dependent synaptic plasticity (13, 17). We previously reported that V404M, the Kv4.2 mutation associated with epilepsy and autism, impairs CSI, but the underlying m...

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Section: Resultssupporting

confidence: 89%

Section: Increase In Side-chain Volume Contributes Substantially To Fsupporting

confidence: 90%

supporting

confidence: 83%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Kv4.2 autism and epilepsy mutation enhances inactivation of closed channels but impairs access to inactivated state after opening

Lin

Cannon

Papazian

2018

Proc. Natl. Acad. Sci. U.S.A.

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Altered closed state inactivation gating in Kv4.2 channels results in developmental and epileptic encephalopathies in human patients

2022

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Kv4.2 subunits, encoded by KCND2, serve as the pore‐forming components of voltage‐gated, inactivating ISA K+ channels expressed in the brain. ISA channels inactivate without opening in response to subthreshold excitatory input, temporarily increasing neuronal excitability, the back propagation of action potentials, and Ca2+ influx into dendrites, thereby regulating mechanisms of spike timing‐dependent synaptic plasticity. As previously described, a de novo variant in Kv4.2, p.Val404Met, is associated with an infant‐onset developmental and epileptic encephalopathy in monozygotic twin boys. The p.Val404Met variant enhances inactivation directly from closed states, but dramatically impairs inactivation after channel opening. We now report the identification of a closely related, novel, de novo variant in Kv4.2, p.Val402Leu, in a boy with an early‐onset pharmacoresistant epilepsy that evolved to an epileptic aphasia syndrome (Continuous Spike Wave during Sleep Syndrome). Like p.Val404Met, the p.Val402Leu variant increases the rate of inactivation from closed states, but significantly slows inactivation after the pore opens. Although quantitatively the p.Val402Leu mutation alters channel kinetics less dramatically than p.Val404Met, our results strongly support the conclusion that p.Val402Leu and p.Val404Met cause the clinical features seen in the affected individuals and underscore the importance of closed state inactivation in ISA channels in normal brain development and function.

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Isoliquiritigenin, an active ingredient of Glycyrrhiza, elicits antinociceptive effects via inhibition of Nav channels

Miyamura

Hitomi

Omiya

et al. 2021

Naunyn-Schmiedeberg's Arch Pharmacol

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Modeling-independent elucidation of inactivation pathways in recombinant and native A-type Kv channels

Cited by 24 publications

References 53 publications

Kv4.2 autism and epilepsy mutation enhances inactivation of closed channels but impairs access to inactivated state after opening

Kv4.2 autism and epilepsy mutation enhances inactivation of closed channels but impairs access to inactivated state after opening

Altered closed state inactivation gating in Kv4.2 channels results in developmental and epileptic encephalopathies in human patients

Isoliquiritigenin, an active ingredient of Glycyrrhiza, elicits antinociceptive effects via inhibition of Nav channels

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