Voltage Sensor Inactivation in Potassium Channels

Bähring, Robert; Barghaan, Jan; Westermeier, Regina; Wollberg, Jessica

doi:10.3389/fphar.2012.00100

Cited by 28 publications

(31 citation statements)

References 97 publications

(142 reference statements)

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“…Closed-state preopen inactivation, which is commonly called U-type inactivation, is observed in many channels and occurs from preopen closed states at modestly depolarized membrane potentials (38,39). However, U-type inactivation is clearly distinct from the BK channel-related closedstate C-type inactivation observed in this study and also the common open-state C-type inactivation observed in most other channels, in that (i) it is insensitive to mutations at the Shaker T449 and W434 positions, (ii) it is not facilitated by a decrease in external K + concentration (38,40), and (iii) it likely occurs through a selectivity filter-independent mechanism involving disengagement of the voltage sensor and activation gate when the voltage sensor is in a partially activated (preopen) state (38,39).…”

Section: Discussionmentioning

confidence: 99%

Closed state-coupled C-type inactivation in BK channels

Yan

Aldrich

2016

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

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Ion channels regulate ion flow by opening and closing their pore gates. K + channels commonly possess two pore gates, one at the intracellular end for fast channel activation/deactivation and the other at the selectivity filter for slow C-type inactivation/recovery. The large-conductance calcium-activated potassium (BK) channel lacks a classic intracellular bundle-crossing activation gate and normally show no C-type inactivation. We hypothesized that the BK channel's activation gate may spatially overlap or coexist with the C-type inactivation gate at or near the selectivity filter. We induced C-type inactivation in BK channels and studied the relationship between activation/deactivation and C-type inactivation/ recovery. We observed prominent slow C-type inactivation/recovery in BK channels by an extreme low concentration of extracellular K + together with a Y294E/K/Q/S or Y279F mutation whose equivalent in Shaker channels (T449E/K/D/Q/S or W434F) caused a greatly accelerated rate of C-type inactivation or constitutive C-inactivation. C-type inactivation in most K + channels occurs upon sustained membrane depolarization or channel opening and then recovers during hyperpolarized membrane potentials or channel closure. However, we found that the BK channel C-type inactivation occurred during hyperpolarized membrane potentials or with decreased intracellular calcium ([Ca 2+ ] i ) and recovered with depolarized membrane potentials or elevated [Ca 2+ ] i . Constitutively open mutation prevented BK channels from C-type inactivation. We concluded that BK channel C-type inactivation is closed statedependent and that its extents and rates inversely correlate with channel-open probability. Because C-type inactivation can involve multiple conformational changes at the selectivity filter, we propose that the BK channel's normal closing may represent an early conformational stage of C-type inactivation.I on channels regulate ion flow across membranes through the voltage-or ligand-regulated opening and closing of a conformational constriction site (gate) at the central pore. For most K + channels, the pore gate located near the pore's intracellular end, called a "bundle-crossing" region, controls fast channel activation/ deactivation (1-4) whereas the existence of another pore gate at the selectivity filter controls slow C-type inactivation and recovery (1, 5-8). C-type inactivation in the widely studied voltagegated Drosophila melanogaster Shaker and mammalian Kv channels or the prokaryotic pH-gated KcsA channels is known to occur from the open state as a result of sustained membrane depolarization or acidic intracellular pH. Extensive structural studies have indicated that C-type inactivation results from changes in ion occupancy and structural rearrangements at or near the selectivity filter (1, 5-8). C-type inactivation is distinct from the fast N-type inactivation, which involves pore blockade by a positively charged N-terminal ball peptide (9, 10).The large-conductance, calcium-activated potassium (BK) channel is acti...

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Section: Discussionmentioning

confidence: 99%

Closed state-coupled C-type inactivation in BK channels

Yan

Aldrich

2016

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

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“…The structural determinants of Kv4 channel inactivation, both without channel opening and including channel opening, have been partially resolved (Barghaan and Bähring, 2009;Barghaan et al, 2008;Dougherty et al, 2008;Gebauer et al, 2004;Kaulin et al, 2008). Combining the existing working models (Bähring et al, 2012;Bähring and Covarrubias, 2011) with NS5806 pharmacology in future experiments may help to elucidate the mode of NS5806 action.…”

Section: Ns5806 Effects On Recombinant Kv4 Channels and Mechanistic Imentioning

confidence: 99%

Hippocampal A-type current and Kv4.2 channel modulation by the sulfonylurea compound NS5806

2012

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“…filter located near the extracellular mouth of the pore (23,(33)(34)(35). In contrast, CSI in Kv4 channels is coupled to voltage sensor conformational changes evoked by depolarization rather than to pore opening (5,10,24).…”

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confidence: 99%

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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Voltage Sensor Inactivation in Potassium Channels

Cited by 28 publications

References 97 publications

Closed state-coupled C-type inactivation in BK channels

Closed state-coupled C-type inactivation in BK channels

Hippocampal A-type current and Kv4.2 channel modulation by the sulfonylurea compound NS5806

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

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