The steady state TTX-sensitive (?window?) sodium current in cardiac Purkinje fibres

Attwell, David; Cohen, Ira S.; Eisner, David; Ohba, Masahiro; Ojeda, Carlos

doi:10.1007/bf00586939

Cited by 455 publications

(239 citation statements)

References 22 publications

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“…This is consistent with G K1 being the largest contributor to the second peak of the notched T wave (T2). Furthermore, the 'well' between T1 and T2 in LQTS2 is closely aligned with the peak of the reactivation of the sodium current (Cyan-dashed line) 24 . We suggest that in LQTS2, reduced G Kr leads to slowing of the rate of repolarization that results in cells spending a longer period of time in the voltage range where sodium channels reactivate (that is, the so-called I Na window current voltage range).…”

Section: Resultsmentioning

confidence: 63%

Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2

et al. 2014

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The heart rhythm disorder long QT syndrome (LQTS) can result in sudden death in the young or remain asymptomatic into adulthood. The features of the surface electrocardiogram (ECG), a measure of the electrical activity of the heart, can be equally variable in LQTS patients, posing well-described diagnostic dilemmas. Here we report a correlation between QT interval prolongation and T-wave notching in LQTS2 patients and use a novel computational framework to investigate how individual ionic currents, as well as cellular and tissue level factors, contribute to notched T waves. Furthermore, we show that variable expressivity of ECG features observed in LQTS2 patients can be explained by as little as 20% variation in the levels of ionic conductances that contribute to repolarization reserve. This has significant implications for interpretation of whole-genome sequencing data and underlies the importance of interpreting the entire molecular signature of disease in any given individual.

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Section: Resultsmentioning

confidence: 63%

Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2

et al. 2014

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“…To focus on possible changes in channel bursting induced by PKA, we measured currents in response to prolonged (150 ms) pulses to Ϫ10 mV, a voltage that is sufficiently positive to avoid measurement of channel reopening that may occur as a consequence of the overlap steady-state activation and inactivation curves (25,27). In whole cell recordings, bursting channels are reflected in sustained inward (I sus ) current under these conditions.…”

Section: Resultsmentioning

confidence: 99%

Modulation of Cardiac Sodium Channel Gating by Protein Kinase A Can Be Altered by Disease-linked Mutation

Tateyama

Rivolta

Clancy

et al. 2003

Journal of Biological Chemistry

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Mutations associated with sodium channel-linked inherited Long-QT syndrome often result in a gain of channel function by disrupting channel inactivation. A small fraction of channels fail to inactivate (burst) at depolarized potentials where normal (wild type) channels fully inactivate. These noninactivating channels give rise to a sustained macroscopic current. We studied the effects of protein kinase A stimulation on sustained current in wild type and three disease-linked C-terminal mutant channels (D1790G, Y1795C, and Y1795H). We show that protein kinase A stimulation differentially affects gating in the mutant channels. Wild type, Y1795C, and Y1795H channels are insensitive to protein kinase A stimulation, whereas "bursting" in the D1790G mutant is markedly enhanced by protein kinase A-dependent phosphorylation. Our results suggest that the charge at position 1790 of the C terminus of the channel modulates the response of the cardiac sodium channel to protein kinase A stimulation and that phosphorylation of residue 36 in the N terminus and residue 525 in the cytoplasmic linker joining domains I and II of the channel ␣ subunit facilitate destabilization of inactivation and thereby increase sustained current.

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“…6C). At voltages within this overlap region, Na ϩ channels are partially activated but not fully inactivated, increasing the potential of persistent window currents (35). At Ϫ50 mV, the peak window current probability predicts that a small percentage (0.1%) of Na v 1.7 channels will be persistently activated.…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of Sodium Channel β Subunits in Dorsal Root Ganglion Sensory Neurons

Zhao

Malinowski

et al. 2012

Journal of Biological Chemistry

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Background: Auxiliary ␤ subunits regulate the voltage-gated sodium channels of dorsal root ganglion (DRG) neurons. Results: ␤ subunits are differentially expressed in subpopulations of DRG neurons and regulate Na v 1.7 channels in an isoformspecific manner. Conclusion: Differential ␤ subunit expression and isoform-specific regulation have important implications for the sodium currents of DRG neurons. Significance: ␤ subunits are important determinants of sodium channel function and sensory neuron excitability.

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The steady state TTX-sensitive (?window?) sodium current in cardiac Purkinje fibres

Cited by 455 publications

References 22 publications

Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2

Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2

Modulation of Cardiac Sodium Channel Gating by Protein Kinase A Can Be Altered by Disease-linked Mutation

Differential Expression of Sodium Channel β Subunits in Dorsal Root Ganglion Sensory Neurons

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