Tetrodotoxin-sensitive α-subunits of voltage-gated sodium channels are relevant for inhibition of cardiac sodium currents by local anesthetics

Stoetzer, Carsten; Doll, Thorben; Stueber, Thomas; Herzog, Christine; Echtermeyer, Frank; Greulich, Franziska; Rudat, C; Kispert, Andreas; Wegner, Florian; Leffler, Andreas

doi:10.1007/s00210-016-1231-9

Cited by 10 publications

(3 citation statements)

References 40 publications

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“…Remarkably, when experimentally tested tafluprost blocked the corresponding currents at both NaV1.5 and TASK-1, although with a higher potency for the latter. The differential activity of tafluprost upon both ion channels (as well as its higher potency as compared with the local anesthetic bupivacaine (Stoetzer et al, 2016)) roughly agrees with the theoretical binding energies predicted by the docking simulations. Noteworthy, although tafluprost was clearly less active in NaV1.5 than in TASK-1, it still shows a potency in a similar range as that shown by the well-known sodium channel blocker bupivacaine (Zhang et al, 2014).…”

Section: Discussionsupporting

confidence: 75%

A New Strategy for Multitarget Drug Discovery/Repositioning Through the Identification of Similar 3D Amino Acid Patterns Among Proteins Structures: The Case of Tafluprost and its Effects on Cardiac Ion Channels

et al. 2022

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The identification of similar three-dimensional (3D) amino acid patterns among different proteins might be helpful to explain the polypharmacological profile of many currently used drugs. Also, it would be a reasonable first step for the design of novel multitarget compounds. Most of the current computational tools employed for this aim are limited to the comparisons among known binding sites, and do not consider several additional important 3D patterns such as allosteric sites or other conserved motifs. In the present work, we introduce Geomfinder2.0, which is a new and improved version of our previously described algorithm for the deep exploration and discovery of similar and druggable 3D patterns. As compared with the original version, substantial improvements that have been incorporated to our software allow: (i) to compare quaternary structures, (ii) to deal with a list of pairs of structures, (iii) to know how druggable is the zone where similar 3D patterns are detected and (iv) to significantly reduce the execution time. Thus, the new algorithm achieves up to 353x speedup as compared to the previous sequential version, allowing the exploration of a significant number of quaternary structures in a reasonable time. In order to illustrate the potential of the updated Geomfinder version, we show a case of use in which similar 3D patterns were detected in the cardiac ions channels NaV1.5 and TASK-1. These channels are quite different in terms of structure, sequence and function and both have been regarded as important targets for drugs aimed at treating atrial fibrillation. Finally, we describe the in vitro effects of tafluprost (a drug currently used to treat glaucoma, which was identified as a novel putative ligand of NaV1.5 and TASK-1) upon both ion channels’ activity and discuss its possible repositioning as a novel antiarrhythmic drug.

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Section: Discussionsupporting

confidence: 75%

A New Strategy for Multitarget Drug Discovery/Repositioning Through the Identification of Similar 3D Amino Acid Patterns Among Proteins Structures: The Case of Tafluprost and its Effects on Cardiac Ion Channels

et al. 2022

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“…Several studies reported that other Na v 1. x isoforms may be expressed in cardiac cells in addition to Na v 1.5, such as Na v 1.1 (Westenbroek et al, 2013), Na v 1.2 (Stoetzer et al, 2016), Na v 1.3 (Westenbroek et al, 2013), Na v 1.4 (Westenbroek et al, 2013), Na v 1.6 (Westenbroek et al, 2013), and Na v 1.8 (Yang et al, 2012). Although we performed the aforementioned I Na recordings in the presence of 50 nM TTX, which efficiently inhibits Na v 1.1 (IC 50 ∼10 nM), Na v 1.2 (IC 50 ∼10 nM), Na v 1.3 (IC 50 ∼10 nM), and Na v 1.6 (IC 50 ∼5 nM), I Na from Na v 1.4 (IC 50 ∼25 nM) and Na v 1.8 (IC 50 > 50 μM) could still be present.…”

Section: Resultsmentioning

confidence: 99%

A Distinct Pool of Nav1.5 Channels at the Lateral Membrane of Murine Ventricular Cardiomyocytes

et al. 2019

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Background: In cardiac ventricular muscle cells, the presence of voltage-gated sodium channels Na v 1.5 at the lateral membrane depends in part on the interaction between the dystrophin–syntrophin complex and the Na v 1.5 C-terminal PDZ-domain-binding sequence Ser-Ile-Val (SIV motif). α1-Syntrophin, a PDZ-domain adaptor protein, mediates the interaction between Na v 1.5 and dystrophin at the lateral membrane of cardiac cells. Using the cell-attached patch-clamp approach on cardiomyocytes expressing Na v 1.5 in which the SIV motif is deleted (ΔSIV), sodium current (I Na ) recordings from the lateral membrane revealed a SIV-motif-independent I Na . Since immunostaining has suggested that Na v 1.5 is expressed in transverse (T-) tubules, this remaining I Na might be carried by channels in the T-tubules. Of note, a recent study using heterologous expression systems showed that α1-syntrophin also interacts with the Na v 1.5 N-terminus, which may explain the SIV-motif independent I Na at the lateral membrane of cardiomyocytes. Aim: To address the role of α1-syntrophin in regulating the I Na at the lateral membrane of cardiac cells. Methods and Results: Patch-clamp experiments in cell-attached configuration were performed on the lateral membranes of wild-type, α1-syntrophin knockdown, and ΔSIV ventricular mouse cardiomyocytes. Compared to wild-type, a reduction of the lateral I Na was observed in myocytes from α1-syntrophin knockdown hearts. Similar to ΔSIV myocytes, a remaining I Na was still recorded. In addition, cell-attached I Na recordings from lateral membrane did not differ significantly between non-detubulated and detubulated ΔSIV cardiomyocytes. Lastly, we obtained evidence suggesting that cell-attached patch-clamp experiments on the lateral membrane cannot record currents carried by channels in T-tubules such as calcium channels. Conclusion: Altogether, these results suggest the presence of a sub-pool of sodium channels at the lateral membrane of cardiomyocytes that is independent of α1-syntrophin and the PDZ-binding motif of Na v 1.5, located in membrane domains outside of T-tubules. The question of a T-tubular pool of Na v 1.5 channels, however, remains open.

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“…Kirchhof et al reported that a peptide that activates Nav1.3 and Nav1.6 can induce positive inotropy without provoking arrhythmias [ 7 ]. We have previously demonstrated that Nav1.5 and brain-type subunits are differentially inhibited Na + channel inhibitors including local anesthetics [ 8 ]. Brain-type subunits may also be relevant for the emergence and treatment of arrhythmias [ 9 , 10 , 11 ], and they were suggested to be relevant for the emergence of pro-arrhythmic non-inactivating late Na + currents in cardiomyocytes [ 12 , 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

A Possible Role of Tetrodotoxin-Sensitive Na+ Channels for Oxidation-Induced Late Na+ Currents in Cardiomyocytes

Schneider,

Hage,

Stein

et al. 2024

IJMS

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An accumulation of reactive oxygen species (ROS) in cardiomyocytes can induce pro-arrhythmogenic late Na+ currents by removing the inactivation of voltage-gated Na+ channels including the tetrodotoxin (TTX)-resistant cardiac α-subunit Nav1.5 as well as TTX-sensitive α-subunits like Nav1.2 and Nav1.3. Here, we explored oxidant-induced late Na+ currents in mouse cardiomyocytes and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as well as in HEK 293 cells expressing Nav1.2, Nav1.3, or Nav1.5. Na+ currents in mouse cardiomyocytes and hiPSC-CMs treated with the oxidant chloramine T (ChT) developed a moderate reduction in peak current amplitudes accompanied by large late Na+ currents. While ChT induced a strong reduction in peak current amplitudes but only small persistent currents on Nav1.5, both Nav1.2 and Nav1.3 produced increased peak current amplitudes and large persistent currents following oxidation. TTX (300 nM) blocked ChT-induced late Na+ currents significantly stronger as compared to peak Na+ currents in both mouse cardiomyocytes and hiPSC-CMs. Similar differences between Nav1.2, Nav1.3, and Nav1.5 regarding ROS sensitivity were also evident when oxidation was induced with UVA-light (380 nm) or the cysteine-selective oxidant nitroxyl (HNO). To conclude, our data on TTX-sensitive Na+ channels expressed in cardiomyocytes may be relevant for the generation of late Na+ currents following oxidative stress.

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Tetrodotoxin-sensitive α-subunits of voltage-gated sodium channels are relevant for inhibition of cardiac sodium currents by local anesthetics

Cited by 10 publications

References 40 publications

A New Strategy for Multitarget Drug Discovery/Repositioning Through the Identification of Similar 3D Amino Acid Patterns Among Proteins Structures: The Case of Tafluprost and its Effects on Cardiac Ion Channels

A New Strategy for Multitarget Drug Discovery/Repositioning Through the Identification of Similar 3D Amino Acid Patterns Among Proteins Structures: The Case of Tafluprost and its Effects on Cardiac Ion Channels

A Distinct Pool of Nav1.5 Channels at the Lateral Membrane of Murine Ventricular Cardiomyocytes

A Possible Role of Tetrodotoxin-Sensitive Na+ Channels for Oxidation-Induced Late Na+ Currents in Cardiomyocytes

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