JZTX-V Targets the Voltage Sensor in Kv4.2 to Inhibit Ito Potassium Channels in Cardiomyocytes

Zhang, Yiya; Luo, Ji; He, Jun; Zeng, Xin

doi:10.3389/fphar.2019.00357

Cited by 4 publications

(5 citation statements)

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“…In this study, the effects of JZTX-V on the wild-type Kv4.3 current expressed in HEK293T cells were studied. The results showed that the IC 50 (9.6 ± 1.2 nM) of Kv4.3 inhibited by JZTX-V was smaller than the IC 50 (13 ± 1.7 nM) of Kv4.2 [ 19 ]. Moreover, under the same detection conditions, it was also lower than other animal toxins that inhibited Kv4.3, such as Ctri9577 (IC 50 = 1.34 ± 0.03 μM) [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of JZTX-V on the wild type Kv4.3 Expressed in HEK293T and Molecular Determinants in the Voltage-sensing Domains of Kv4.3 Interacting with JZTX-V

Wenmei

Siqin

et al. 2022

Channels

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JZTX-V is a toxin isolated from the venom of the Chinese spider Chilobrachys jingzhao . Previous studies had shown that JZTX-V could inhibit the transient outward potassium current of Kv4.2 and Kv4.3 expressed in Xenopus oocytes but had no effects on Kv1.2–1.4. However, the underlying action mechanism of JZTX-V on Kv4.3 remains unclear. In our study, JZTX-V could inhibit not only transient outward potassium currents evoked in small-sized DRG neurons but also Kv4.3-encoded currents expressed in HEK293T cells in the concentration and voltage dependence. The half maximal inhibitory concentration of JZTX-V on Kv4.3 was 9.6 ± 1.2 nM. In addition, the time course for JZTX-V inhibition and release of inhibition after washout were 15.8 ± 1.54 s and 58.8 ± 4.35 s. Electrophysiological assays indicated that 25 nM JZTX-V could shift significantly the voltage dependence of steady-state activation and steady-state inactivation to depolarization. Meanwhile, 25 nM JZTX-V decreased markedly the time constant of activation and inactivation but had no effect on the time constant of recovery from inactivation. To study the molecular determinants of Kv4.3, we performed alanine scanning on a conserved motif of Kv4.3 and assayed the affinity between mutants and JZTX-V. The results not only showed that I273, L275, V283, and F287 were molecular determinants in the conserved motif of Kv4.3 for interacting with JZTX-V but also speculated the underlying action mechanism that the hydrophobic interaction and steric effects played key roles in the binding of JZTX-V with Kv4.3. In summary, our studies have laid a scientific theoretical foundation for further research on the interaction mechanism between JZTX-V and Kv4.3.

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Section: Discussionmentioning

confidence: 99%

Effects of JZTX-V on the wild type Kv4.3 Expressed in HEK293T and Molecular Determinants in the Voltage-sensing Domains of Kv4.3 Interacting with JZTX-V

Wenmei

Siqin

et al. 2022

Channels

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“…Although cardiac I to,f and I to,s channels are differently expressed in various mammalian species and contribute to the heterogeneity of the AP and its waveforms, they have a potential importance in the genesis of cardiac arrhythmias. In addition, it has recently been demonstrated by Zhang et al (2019a), that jingzhaotoxin-V (JZTX-V), a selective inhibitor of A-type potassium channel, plays a crucial role in the regulation of I to potassium channels, supporting its use as a new potential and novel antiarrhythmic agent.…”

Section: Kcnd2-d3mentioning

confidence: 99%

ArrhythmoGenoPharmacoTherapy

Tósaki

2020

Front. Pharmacol.

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This review is focusing on the understanding of various factors and components governing and controlling the occurrence of ventricular arrhythmias including (i) the role of various ion channel-related changes in the action potential (AP), (ii) electrocardiograms (ECGs), (iii) some important arrhythmogenic mediators of reperfusion, and pharmacological approaches to their attenuation. The transmembrane potential in myocardial cells is depending on the cellular concentrations of several ions including sodium, calcium, and potassium on both sides of the cell membrane and active or inactive stages of ion channels. The movements of Na + , K + , and Ca 2+ via cell membranes produce various currents that provoke AP, determining the cardiac cycle and heart function. A specific channel has its own type of gate, and it is opening and closing under specific transmembrane voltage, ionic, or metabolic conditions. APs of sinoatrial (SA) node, atrioventricular (AV) node, and Purkinje cells determine the pacemaker activity (depolarization phase 4) of the heart, leading to the surface manifestation, registration, and evaluation of ECG waves in both animal models and humans. AP and ECG changes are key factors in arrhythmogenesis, and the analysis of these changes serve for the clarification of the mechanisms of antiarrhythmic drugs. The classification of antiarrhythmic drugs may be based on their electrophysiological properties emphasizing the connection between basic electrophysiological activities and antiarrhythmic properties. The review also summarizes some important mechanisms of ventricular arrhythmias in the ischemic/ reperfused myocardium and permits an assessment of antiarrhythmic potential of drugs used for pharmacotherapy under experimental and clinical conditions.

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“…On the other hand, depolarizing voltages could partially or fully counteract toxin’s inhibition on voltage sensor, resulting in different inhibition on the currents at different voltages, defined as voltage-dependent inhibition ( Phillips et al, 2005 ). Gating modifier toxins of K V 4 channels, such as Ctri9557, JZTX-XII, JZTX-V and PaTx-1, all likely act in this way ( Diochot et al, 1999 ; Yuan et al, 2007 ; Xie et al, 2014 ; Zhang et al, 2019b ). It could be reasonably speculated that a larger I-V/G-V shift and less voltage-dependent inhibition would be observed in toxins stabilizing the resting voltage sensor much more stably, and vice versa.…”

Section: Discussionmentioning

confidence: 99%

“…Animal venoms are rich in peptide toxins acting on various types of ion channels and receptors. Up to date, lots of venom-derived peptide antagonists for the K V 4 channels have been characterized ( Swartz and MacKinnon, 1995 ; Sanguinetti et al, 1997 ; Escoubas et al, 2002 ; Yuan et al, 2007 ; Bougis and Martin-Eauclaire, 2015 ; Zhang et al, 2019b ). They could be roughly classified into two groups as pore blockers and gating modifiers based on their action modes.…”

Section: Introductionmentioning

confidence: 99%

“…For example, AmmTX3 inhibits less K V 4 currents in heterologous expression system than that in native neurons, which might be caused by the presence of auxiliary subunits DPP6/10 in native tissue but not in cultured cell lines helps to rearrange the structure of the channel pore, allowing for a better residence of toxin in it ( Maffie et al, 2013 ). On the other hand, lots of spider toxins were characterized as gating modifiers which inhibit K V 4 channels’ currents by trapping their voltage sensor in a resting state, hindering its activation in response to membrane depolarizations, such as Heteropodatoxins (HpTx1-3), JZTX-V, JZTX-XII, HaTx1, and ScTx ( Swartz and MacKinnon, 1995 ; Sanguinetti et al, 1997 ; Escoubas et al, 2002 ; Zarayskiy et al, 2005 ; Yuan et al, 2007 ; Zhang et al, 2019b ). Based on the action mechanism, these toxins would usually shift the voltage-dependent activation and/or inactivation kinetics of the channel.…”

Section: Introductionmentioning

confidence: 99%

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Variation of Two S3b Residues in KV4.1–4.3 Channels Underlies Their Different Modulations by Spider Toxin κ-LhTx-1

Zhang

Zhao

et al. 2021

Front. Pharmacol.

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The naturally occurred peptide toxins from animal venoms are valuable pharmacological tools in exploring the structure-function relationships of ion channels. Herein we have identified the peptide toxin κ-LhTx-1 from the venom of spider Pandercetes sp (the Lichen huntsman spider) as a novel selective antagonist of the KV4 family potassium channels. κ-LhTx-1 is a gating-modifier toxin impeded KV4 channels’ voltage sensor activation, and mutation analysis has confirmed its binding site on channels’ S3b region. Interestingly, κ-LhTx-1 differently modulated the gating of KV4 channels, as revealed by toxin inhibiting KV4.2/4.3 with much more stronger voltage-dependence than that for KV4.1. We proposed that κ-LhTx-1 trapped the voltage sensor of KV4.1 in a much more stable resting state than that for KV4.2/4.3 and further explored the underlying mechanism. Swapping the non-conserved S3b segments between KV4.1(280FVPK283) and KV4.3(275VMTN278) fully reversed their voltage-dependence phenotypes in inhibition by κ-LhTx-1, and intensive mutation analysis has identified P282 in KV4.1, D281 in KV4.2 and N278 in KV4.3 being the key residues. Furthermore, the last two residues in this segment of each KV4 channel (P282/K283 in KV4.1, T280/D281 in KV4.2 and T277/N278 in KV4.3) likely worked synergistically as revealed by our combinatorial mutations analysis. The present study has clarified the molecular basis in KV4 channels for their different modulations by κ-LhTx-1, which have advanced our understanding on KV4 channels’ structure features. Moreover, κ-LhTx-1 might be useful in developing anti-arrhythmic drugs given its high affinity, high selectivity and unique action mode in interacting with the KV4.2/4.3 channels.

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JZTX-V Targets the Voltage Sensor in Kv4.2 to Inhibit Ito Potassium Channels in Cardiomyocytes

Cited by 4 publications

References 42 publications

Effects of JZTX-V on the wild type Kv4.3 Expressed in HEK293T and Molecular Determinants in the Voltage-sensing Domains of Kv4.3 Interacting with JZTX-V

Effects of JZTX-V on the wild type Kv4.3 Expressed in HEK293T and Molecular Determinants in the Voltage-sensing Domains of Kv4.3 Interacting with JZTX-V

ArrhythmoGenoPharmacoTherapy

Variation of Two S3b Residues in KV4.1–4.3 Channels Underlies Their Different Modulations by Spider Toxin κ-LhTx-1

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