A hot topic

Egri, Csilla; Ruben, Peter C.

doi:10.4161/chan.19827

Cited by 14 publications

(6 citation statements)

References 104 publications

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“…Pathogenic LoF or GoF of sodium channels could also occur under hyperthermia, such as fever. Although it is evident that increased temperature plays a major role in FS pathogenesis, studies on the effect of FT on the gating mechanisms of sodium channel subtypes or their mutants associated with FS are largely lacking 36 . Thomas et al .…”

Section: Introductionmentioning

confidence: 99%

Differential roles of NaV1.2 and NaV1.6 in regulating neuronal excitability at febrile temperature and distinct contributions to febrile seizures

Yang

Tian

et al. 2018

Sci Rep

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Dysregulation of voltage-gated sodium channels (VGSCs) is associated with multiple clinical disorders, including febrile seizures (FS). The contribution of different sodium channel subtypes to environmentally triggered seizures is not well understood. Here we demonstrate that somatic and axonal sodium channels primarily mediated through NaV1.2 and NaV1.6 subtypes, respectively, behave differentially at FT, and might play distinct roles in FS generation. In contrast to sodium channels on the main axonal trunk, somatic ones are more resistant to inactivation and display significantly augmented currents, faster gating rates and kinetics of recovery from inactivation at FT, features that promote neuronal excitabilities. Pharmacological inhibition of NaV1.2 by Phrixotoxin-3 (PTx3) suppressed FT-induced neuronal hyperexcitability in brain slice, while up-regulation of NaV1.2 as in NaV1.6 knockout mice showed an opposite effect. Consistently, NaV1.6 knockout mice were more susceptible to FS, exhibiting much lower temperature threshold and shorter onset latency than wildtype mice. Neuron modeling further suggests that NaV1.2 is the major subtype mediating FT-induced neuronal hyperexcitability, and predicts potential outcomes of alterations in sodium channel subtype composition. Together, these data reveal a role of native NaV1.2 on neuronal excitability at FT and its important contribution to FS pathogenesis.

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Section: Introductionmentioning

confidence: 99%

Differential roles of NaV1.2 and NaV1.6 in regulating neuronal excitability at febrile temperature and distinct contributions to febrile seizures

Yang

Tian

et al. 2018

Sci Rep

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“…The temperature sensitivity of voltage-gated sodium channels such as SCN5A in mammals is still under debate with several studies not finding any effect of temperature while others finding strong effects (Egri and Ruben, 2012). For poultry, SCN5A was found to be differentially expressed in the breast tissue between control broiler embryos, incubated at 37.8 • C and heat incubated embryos (39.5 • C, 12 h, ED7-16) (Loyau et al, 2016).…”

Section: Scn5amentioning

confidence: 99%

Influence of temperature during incubation on the mRNA levels of temperature sensitive ion channels in the brain of broiler chicken embryos

Verlinden

Norton

Larsen

et al. 2022

Comparative Biochemistry and Physiology Part A: Molecular &

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“…Some SCN5A mutations may induce BrS-associated symptoms especially during fever episodes, with may be due to changes in I Na channel gating properties in response to increasing temperature ( 120 , 121 ). We and others have shown that specific SCN5A mutations promote slow inactivation of I Na at higher temperatures (i.e., enhanced slow inactivation), thereby causing reduced peak I Na availability ( 122 , 123 ).…”

Section: Variable Expressivity In Scn5a Channelopamentioning

confidence: 99%

“…We and others have shown that specific SCN5A mutations promote slow inactivation of I Na at higher temperatures (i.e., enhanced slow inactivation), thereby causing reduced peak I Na availability ( 122 , 123 ). To date, specific LQT3-associated SCN5A mutations which display enhanced temperature sensitivities have not been described ( 121 ). In general, increased temperature does not affect the ratio between late and peak I Na ( 124 ), but enhances the transmural repolarization dispersion thus facilitating the occurrence of torsade de pointes (TdP) during LQTS ( 125 ).…”

Section: Variable Expressivity In Scn5a Channelopamentioning

confidence: 99%

Disease Modifiers of Inherited SCN5A Channelopathy

Verkerk

Amin

Remme

2018

Front. Cardiovasc. Med.

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To date, a large number of mutations in SCN5A, the gene encoding the pore-forming α-subunit of the primary cardiac Na+ channel (NaV1.5), have been found in patients presenting with a wide range of ECG abnormalities and cardiac syndromes. Although these mutations all affect the same NaV1.5 channel, the associated cardiac syndromes each display distinct phenotypical and biophysical characteristics. Variable disease expressivity has also been reported, where one particular mutation in SCN5A may lead to either one particular symptom, a range of various clinical signs, or no symptoms at all, even within one single family. Additionally, disease severity may vary considerably between patients carrying the same mutation. The exact reasons are unknown, but evidence is increasing that various cardiac and non-cardiac conditions can influence the expressivity and severity of inherited SCN5A channelopathies. In this review, we provide a summary of identified disease entities caused by SCN5A mutations, and give an overview of co-morbidities and other (non)-genetic factors which may modify SCN5A channelopathies. A comprehensive knowledge of these modulatory factors is not only essential for a complete understanding of the diverse clinical phenotypes associated with SCN5A mutations, but also for successful development of effective risk stratification and (alternative) treatment paradigms.

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A hot topic

Cited by 14 publications

References 104 publications

Differential roles of NaV1.2 and NaV1.6 in regulating neuronal excitability at febrile temperature and distinct contributions to febrile seizures

Differential roles of NaV1.2 and NaV1.6 in regulating neuronal excitability at febrile temperature and distinct contributions to febrile seizures

Influence of temperature during incubation on the mRNA levels of temperature sensitive ion channels in the brain of broiler chicken embryos

Disease Modifiers of Inherited SCN5A Channelopathy

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