Gating pore currents, a new pathological mechanism underlying cardiac arrhythmias associated with dilated cardiomyopathy

Moreau, Adrien; Gosselin-Badaroudine, Pascal; Chahine, Mohamed

doi:10.1080/19336950.2015.1031937

Cited by 11 publications

(9 citation statements)

References 45 publications

(75 reference statements)

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“…However, many membrane transport proteins permit the simultaneous passage of a proton with a different ion or ions, which will contaminate or completely obscure the proton current. Omega currents from voltage-gated cation channels are a class of proton currents that have been postulated to cause several human diseases (George, 2012; Jurkat-Rott et al, 2010; Moreau et al, 2015; Sokolov et al, 2007; Struyk et al, 2008), but have not been observed without destroying or blocking the ion conducting pore domain. Therefore, we used our approach to determine whether these gain-of-function voltage sensor domain mutations create omega proton currents in a channel with a functioning central pore.…”

Section: Resultsmentioning

confidence: 99%

“…Gain of function mutations that create unregulated proton pores in voltage-gated cation channels have been implicated in myotonias, periodic paralysis, and some forms of Long QT Syndrome (Jurkat-Rott et al, 2012; Jurkat-Rott and Lehmann-Horn, 2010). Although these tiny “omega” currents are completely obscured by the central cation-conducting pore, the chronic leak of protons through these pores has been hypothesized to be sufficient to alter cardiac and muscular electrical activity (George, 2012; Jurkat-Rott et al, 2010; Moreau et al, 2015; Sokolov et al, 2007; Struyk et al, 2008). Given their varied physiological roles, proton transport proteins are viable therapeutic targets for treating human diseases—the most successful target has been the gastric proton pump, where irreversible inhibition of this proton flux mitigates gastrointestinal reflux disease (Sachs et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Fluorescent Visualization of Cellular Proton Fluxes

Zhang

Bellvé

Fogarty

et al. 2016

Cell Chemical Biology

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SummaryCells use plasma membrane proton fluxes to maintain cytoplasmic and extracellular pH and to mediate the co-transport of metabolites and ions. Because proton-coupled transport often involves movement of multiple substrates, traditional electrical measurements provide limited information about proton transport at the cell surface. Here we visualize voltage-dependent proton fluxes over the entire landscape of a cell by covalently attaching small molecule fluorescent pH sensors to the cell's glycocalyx. We found that the extracellularly-facing sensors enable real-time detection of proton accumulation and depletion at the plasma membrane, providing an indirect readout of channel and transporter activity that correlated with whole-cell proton current. Moreover, the proton wavefront emanating from one cell was readily visible as it crossed over nearby cells. Given that any small molecule fluorescent sensor can be covalently attached to a cell's glycocalyx, our approach is readily adaptable to visualize most electrogenic and non-electrogenic transport events at the plasma membrane.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fluorescent Visualization of Cellular Proton Fluxes

Zhang

Bellvé

Fogarty

et al. 2016

Cell Chemical Biology

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“…Although the arginine residues of the S4 segments in DⅢ and DIV appear to have domain-specific important roles in the fast inactivation, those in DⅠ and DⅡ do not appear to have important roles [5,6]. In addition, the role of the S4 segments in Na v s differs with respect to gating pore currents (or ω-currents) [68][69][70].…”

Section: Lack Of Gating Pore Currents By Mutations Of Arginine Residumentioning

confidence: 96%

“…Substitutions of the R1 residue of S4 in the Shaker channel conduct protons or non-selective cations directly through the voltage sensor domains (gating pore or ω-pore), not through alpha (ɑ)-pore, depending on substituted residues. It is thought that disrupted interaction of substituted arginine with pGCTC may create a water crevice spanning the membrane and open a continuous aqueous pathway [68][69][70][71][72]. On the other hand, in Na v s, gating pore currents were first observed in substitutions of R1 and R2 in Na v 1.2 DⅡS4 [73].…”

Section: Lack Of Gating Pore Currents By Mutations Of Arginine Residumentioning

confidence: 99%

Role of the voltage sensor module in Na_v domain IV on fast inactivation in sodium channelopathies: The implication of closed-state inactivation

et al. 2019

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The segment 4 (S4) voltage sensor in voltage-gated sodium channels (Na v s) have domain-specific functions, and the S4 segment in domain DIV (DIVS4) plays a key role in the activation and fast inactivation processes through the coupling of arginine residues in DIVS4 with residues of putative gating charge transfer center (pGCTC) in DIVS1-3. In addition, the first four arginine residues (R1-R4) in Na v DIVS4 have position-specific functions in the fast inactivation process, and mutations in these residues are associated with diverse phenotypes of Na v-related diseases (sodium channelopathies). R1 and R2 mutations commonly display a delayed fast inactivation, causing a gain-of-function, whereas R3 and R4 mutations commonly display a delayed recovery from inactivation and profound use-dependent current attenuation, causing a severe loss-offunction. In contrast, mutations of residues of pGCTC in Na v DIVS1-3 can also alter fast inactivation. Such alterations in fast inactivation may be caused by disrupted interactions of DIVS4 with DIVS1-3. Despite fast inactivation of Na v s occurs from both the open-state (open-state inactivation; OSI) and closed state (closed-state inactivation; CSI), changes in CSI have received considerably less attention than those in OSI in the pathophysiology of sodium channelopathies. CSI can be altered by mutations of arginine residues in DIVS4 and residues of pGCTC in Na v s, and altered CSI can be an underlying primary biophysical defect of sodium channelopathies. Therefore, CSI should receive focus in order to clarify the pathophysiology of sodium channelopathies.

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“…Mutations in genes encoding these channels can lead to a variety of severe illnesses. Na V channels are considered as potential drug targets for diseases [including pain syndromes, cardiac disorders, and epilepsy (1,2)] that require potent and selective Na V channel inhibitors. Phoneutria nigriventer, also known as the Brazilian wandering spider, produces potent venom that is responsible for many of South Brazil's most severe envenomations in humans (3,4).…”

mentioning

confidence: 99%

Where cone snails and spiders meet: design of small cyclic sodium‐channel inhibitors

et al. 2018

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A 13 aa residue voltage‐gated sodium (Nav) channel inhibitor peptide, Pn, containing 2 disulfide bridges was designed by using a chimeric approach. This approach was based on a common pharmacophore deduced from sequence and secondary structural homology of 2 NaV inhibitors: Conus kinoshitai toxin IIIA, a 14 residue cone snail peptide with 3 disulfide bonds, and Phoneutria nigriventer toxin 1, a 78 residue spider toxin with 7 disulfide bonds. As with the parent peptides, this novel NaV channel inhibitor was active on NaV1.2. Through the generation of 3 series of peptide mutants, we investigated the role of key residues and cyclization and their influence on NaV inhibition and subtype selectivity. Cyclic PnCS1, a 10 residue peptide cyclized via a disulfide bond, exhibited increased inhibitory activity toward therapeutically relevant NaV channel subtypes, including NaV1.7 and NaV1.9, while displaying remarkable serum stability. These peptides represent the first and the smallest cyclic peptide NaV modulators to date and are promising templates for the development of toxin‐based therapeutic agents.—Peigneur, S., Cheneval, O., Maiti, M., Leipold, E., Heinemann, S. H., Lescrinier, E., Herdewijn, P., De Lima, M. E., Craik, D. J., Schroeder, C. I., Tytgat, J. Where cone snails and spiders meet: design of small cyclic sodium‐channel inhibitors. FASEB J. 33, 3693–3703 (2019). http://www.fasebj.org

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Gating pore currents, a new pathological mechanism underlying cardiac arrhythmias associated with dilated cardiomyopathy

Cited by 11 publications

References 45 publications

Fluorescent Visualization of Cellular Proton Fluxes

Fluorescent Visualization of Cellular Proton Fluxes

Role of the voltage sensor module in Na_v domain IV on fast inactivation in sodium channelopathies: The implication of closed-state inactivation

Where cone snails and spiders meet: design of small cyclic sodium‐channel inhibitors

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Gating pore currents, a new pathological mechanism underlying cardiac arrhythmias associated with dilated cardiomyopathy

Cited by 11 publications

References 45 publications

Fluorescent Visualization of Cellular Proton Fluxes

Fluorescent Visualization of Cellular Proton Fluxes

Role of the voltage sensor module in Nav domain IV on fast inactivation in sodium channelopathies: The implication of closed-state inactivation

Where cone snails and spiders meet: design of small cyclic sodium‐channel inhibitors

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Role of the voltage sensor module in Na_v domain IV on fast inactivation in sodium channelopathies: The implication of closed-state inactivation