The Binding of κ-Conotoxin PVIIA and Fast C-Type Inactivation of Shaker K+ Channels are Mutually Exclusive

Koch, E. Dietlind; Olivera, Baldomero M.; Terlau, Heinrich; Conti, Franco

doi:10.1016/s0006-3495(04)74096-5

Cited by 25 publications

(14 citation statements)

References 29 publications

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“…Our study provides a structural model for the chemical shift changes observed upon high-affinity binding of KTX to the chimeric potassium channel KcsA-Kv1.3. Due to their sharing of many important features, such as dependence on the same set of point mutations in the external pore vestibule, or sensitivity to external tetraethylammonium (TEA), a connection between the association of peptidic toxins and C-type inactivation was long assumed, but could not yet be clearly established by using low-affinity toxin peptides (Kurata and Fedida, 2006;Oliva et al, 2005;Koch et al, 2004). These conformational effects could thus far only be studied indirectly because of the lack of a high-resolution structural picture for both toxin binding and C-type inactivation (Kurata and Fedida, 2006).…”

Section: Discussionmentioning

confidence: 99%

The Molecular Mechanism of Toxin-Induced Conformational Changes in a Potassium Channel: Relation to C-Type Inactivation

et al. 2008

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Recently, a solid-state NMR study revealed that scorpion toxin binding leads to conformational changes in the selectivity filter of potassium channels. The exact nature of the conformational changes, however, remained elusive. We carried out all-atom molecular dynamics simulations that enabled us to cover the complete pathway of toxin approach and binding, and we validated our simulation results by using solid-state NMR data and electrophysiological measurements. Our structural model revealed a mechanism of cooperative toxin-induced conformational changes that accounts both for the signal changes observed in solid-state NMR and for the tight interaction between KcsA-Kv1.3 and Kaliotoxin. We show that this mechanism is structurally and functionally closely related to recovery from C-type inactivation. Furthermore, our simulations indicate heterogeneity in the binding modes of Kaliotoxin, which might serve to enhance its affinity for KcsA-Kv1.3 further by entropic stabilization.

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Section: Discussionmentioning

confidence: 99%

The Molecular Mechanism of Toxin-Induced Conformational Changes in a Potassium Channel: Relation to C-Type Inactivation

et al. 2008

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“…To examine the validity of this prediction, we have sought an experimental design that would allow us to separate between the two steps of Cs1 action, namely toxin binding and pore-collapse. To this end, we have employed the Shaker KD M448K mutant, which exhibit accelerated slow inactivation, while retaining high affinity for toxins ( Fig S6A; Koch et al, 2004). While Cs1 binding to unmodified Shaker KD was voltage-insensitive ( Fig.…”

Section: Channel Block By Conkunitzin-s1 Is Slowed By Heavy Watermentioning

confidence: 99%

Pore-modulating toxins exploit inherent slow inactivation to block K⁺channels

Karbat

Altman-Gueta

Fine

et al. 2019

Preprint

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Voltage dependent potassium channels (K v s) gate in response to changes in electrical membrane potential by coupling a voltage-sensing module with a K + -selective pore. Animal toxins targeting K v s are classified to "pore-blockers" that physically plug the ion conduction pathway and "gating modifiers" that disrupt voltage sensor movements. A third group of toxins blocks K + conduction by an unknown mechanism via binding to the channel turrets. Here we show that Cs1, a peptide toxin isolated from cone snail venom, binds at the turrets of K v 1.2 and targets a network of hydrogen bonds that govern water access to the peripheral cavities that surround the central pore. The resulting ectopic water flow triggers an asymmetric collapse of the pore by a process resembling that of inherent slow inactivation. Pore modulation by animal toxins exposes the peripheral cavity of K + channels as a novel pharmacological target and provides a rational framework for drug design.

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“…Interestingly, a bidirectional modulation of ion channels is brought about by a number of conditions, such as changes in the holding potential (Kass, 1987). It is also not restricted to low molecular weight compounds (Koch et al, 2004;Mezler et al, 2012a) and may simply be observed by changing the expression system (Mezler et al, 2012a). Cho and Meriney (2006) reported a 427% attenuation of the deactivation kinetics of calcium currents by roscovitine in Xenopus motorneurons and consequently increased transmitter release.…”

Section: Low Molecular Weight Calcium Channel Blockersmentioning

confidence: 99%

P/Q‐type calcium channel modulators

Nimmrich

Groß

2012

British J Pharmacology

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P/Q-type calcium channels are high-voltage-gated calcium channels contributing to vesicle release at synaptic terminals. A number of neurological diseases have been attributed to malfunctioning of P/Q channels, including ataxia, migraine and Alzheimer's disease. To date, only two specific P/Q-type blockers are known: both are peptides deriving from the spider venom of Agelenopsis aperta, w-agatoxins. Other peptidic calcium channel blockers with activity at P/Q channels are available, albeit with less selectivity. A number of low molecular weight compounds modulate P/Q-type currents with different characteristics, and some exhibit a peculiar bidirectional pattern of modulation. Interestingly, there are a number of therapeutics in clinical use, which also show P/Q channel activity. Because selectivity as well as the exact mode of action is different between all P/Q-type channel modulators, the interpretation of clinical and experimental data is complicated and needs a comprehensive understanding of their target profile. The situation is further complicated by the fact that information on potency varies vastly in the literature, which may be the result of different experimental systems, conditions or the splice variants of the P/Q channel. This review attempts to provide a comprehensive overview of the compounds available that affect the P/Q-type channel and should help with the interpretation of results of in vitro experiments and animal models. It also aims to explain some clinical observations by implementing current knowledge about P/Q channel modulation of therapeutically used non-selective drugs. Chances and challenges of the development of P/Q channel-selective molecules are discussed. AbbreviationsAb, amyloid-b; AD, Alzheimer's disease; CDK, cycline-dependent kinase; LMW, low molecular weight; VGCC, voltage-gated calcium channel IntroductionThe P/Q-type calcium channel (also referred to as Cav2.1) is a presynaptic high-voltage-gated calcium channel, which couples neuronal excitation to secretion of neurotransmitter (Ishikawa et al., 2005). The ion-conducting pore is formed by four domains of the a1A subunit, whereas accessory subunits (b, a2d) modulate channel kinetics and the level of expression. P-type currents were first identified in Purkinje neurons of the cerebellum (Llinás et al., 1989) and are distinguished from Q-type currents identified in cerebellar granule neurons (Randall and Tsien, 1995). Both are characterized by their sensitivity to the venom of Agelenopsis aperta, w-agatoxin IVA (Mintz et al., 1992a), and are generated by ion channels encoded by the CACNA1A gene. A number of splice variants may explain different phenotypic characteristics of P-and Q-type channels (Bourinet et al., 1999). For convenience and because distinction between these channel subtypes is not always clear, we refer throughout this review to P/Q-type channels. Expression of P/Q-type channels often overlaps with its close analogue, the N-type calcium channel. Yet, the P/Q-type channel is preferably expressed in neurons o...

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The Binding of κ-Conotoxin PVIIA and Fast C-Type Inactivation of Shaker K+ Channels are Mutually Exclusive

Cited by 25 publications

References 29 publications

The Molecular Mechanism of Toxin-Induced Conformational Changes in a Potassium Channel: Relation to C-Type Inactivation

The Molecular Mechanism of Toxin-Induced Conformational Changes in a Potassium Channel: Relation to C-Type Inactivation

Pore-modulating toxins exploit inherent slow inactivation to block K⁺channels

P/Q‐type calcium channel modulators

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The Binding of κ-Conotoxin PVIIA and Fast C-Type Inactivation of Shaker K+ Channels are Mutually Exclusive

Cited by 25 publications

References 29 publications

The Molecular Mechanism of Toxin-Induced Conformational Changes in a Potassium Channel: Relation to C-Type Inactivation

The Molecular Mechanism of Toxin-Induced Conformational Changes in a Potassium Channel: Relation to C-Type Inactivation

Pore-modulating toxins exploit inherent slow inactivation to block K+channels

P/Q‐type calcium channel modulators

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Pore-modulating toxins exploit inherent slow inactivation to block K⁺channels