Modulation of Nav1.5 by ?1- and ?3-subunit co-expression in mammalian cells

Ko, Seonghoon; Lenkowski, Paul W.; Lee, Hwa C.; Mounsey, J. Paul; Patel, Manoj K.

doi:10.1007/s00424-004-1348-4

Cited by 65 publications

(63 citation statements)

References 46 publications

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“…They showed that the lack of Na V β3 induced a ≈30% decrease in cardiac Na + peak current amplitude associated with a shift of the steadystate inactivation curve toward negative potentials while other I Na biophysical parameters were not altered, thus confirming previous studies in mammalian heterologous expression system (Ko et al, 2005). As a consequence, Scn3b ] mice exhibited decreased ventricular conduction, shortened ventricular action potential duration, and refractory period and increased incidence of arrhythmias under programmed electrical stimulation in ex vivo Langendorffperfused hearts (Hakim et al, 2008).…”

Section: Scn3b Knockout Mousesupporting

confidence: 77%

Mouse models of SCN5A-related cardiac arrhythmias

Charpentier

Bourgé

Mérot

2008

Progress in Biophysics and Molecular Biology

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Mutations of SCN5A gene, which encodes the α-subunit of the voltage-gated Na channel Na V 1.5, underlie hereditary cardiac arrhythmic syndromes such as the type 3 long QT syndrome, cardiac conduction diseases, the Brugada syndrome, the sick sinus syndrome, a trial standstill, and numerous overlap syndromes. Patch-clamp studies in heterologous expression systems have provided important information to understand the genotype-phenotype relationships of these diseases. However, they could not clarify how SCN5A mutations can be responsible for such a large spectrum of diseases, for the late age of onset or the progressiveness of some of these diseases and for the overlapping syndromes. Genetically modified mice rapidly appeared as promising tools for understanding the pathophysiological mechanisms of cardiac SCN5A-related arrhythmic syndromes and several mouse models have been established. This review presents the results obtained on these models that, for most of them, recapitulate the clinical phenotypes of the patients. This includes two models knocked out for Nav1.5 β1 and β3 auxiliary subunits that are also discussed. Despite their own limitations that we point out, the mouse models still appear as powerful tools to elucidate the pathophysiological mechanisms of SCN5A-related diseases and offer the opportunity to investigate the secondary cellular consequences of SCN5A mutations such as the expression remodeling of other genes. This points out the potential role of these genes in the overall human phenotype. Finally, they constitute useful tools for addressing the role of genetic and environmental modifiers on cardiac electrical activity.

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Section: Scn3b Knockout Mousesupporting

confidence: 77%

Mouse models of SCN5A-related cardiac arrhythmias

Charpentier

Bourgé

Mérot

2008

Progress in Biophysics and Molecular Biology

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“…Conductance as a function of voltage was derived from the current–voltage relationship and fitted by a Boltzmann function as described previously 24. Decays of macroscopic currents were fitted to a single exponential function and time constants were determined 25. For steady‐state inactivation, neurons were held at −120 mV and test potentials from −115 mV to −10 mV for 1 sec at 5 mV increments were applied.…”

Section: Methodsmentioning

confidence: 99%

Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy

Wagnon

Barker

Hounshell

et al. 2015

Ann Clin Transl Neurol

Self Cite

101

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ObjectiveThe early infantile epileptic encephalopathy type 13 (EIEE13, OMIM #614558) results from de novo missense mutations of SCN8A encoding the voltage‐gated sodium channel Nav1.6. More than 20% of patients have recurrent mutations in residues Arg1617 or Arg1872. Our goal was to determine the functional effects of these mutations on channel properties.MethodsClinical exome sequencing was carried out on patients with early‐onset seizures, developmental delay, and cognitive impairment. Two mutations identified here, p.Arg1872Leu and p.Arg1872Gln, and two previously identified mutations, p.Arg1872Trp and p.Arg1617Gln, were introduced into Nav1.6 cDNA, and effects on electrophysiological properties were characterized in transfected ND7/23 cells. Interactions with FGF14, G‐protein subunit Gβγ, and sodium channel subunit β1 were assessed by coimmunoprecipitation.ResultsWe identified two patients with the novel mutation p.Arg1872Leu and one patient with the recurrent mutation p.Arg1872Gln. The three mutations of Arg1872 and the mutation of Arg1617 all impaired the sodium channel transition from open state to inactivated state, resulting in channel hyperactivity. Other observed abnormalities contributing to elevated channel activity were increased persistent current, increased peak current density, hyperpolarizing shift in voltage dependence of activation, and depolarizing shift in steady‐state inactivation. Protein interactions were not affected.InterpretationRecurrent mutations at Arg1617 and Arg1872 lead to elevated Nav1.6 channel activity by impairing channel inactivation. Channel hyperactivity is the major pathogenic mechanism for gain‐of‐function mutations of SCN8A. EIEE13 differs mechanistically from Dravet syndrome, which is caused by loss‐of‐function mutations of SCN1A. This distinction has important consequences for selection of antiepileptic drugs and the development of gene‐ and mutation‐specific treatments.

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“…Some groups have reported that β1 increases Na V 1.5 currents with or without affecting voltage dependence or channel kinetics, while others have reported no effect of β1 on Na V 1.5 current (20,(33)(34)(35)(36)(37). The β1B variant has to date only been studied in coexpression studies with the neuronal sodium channel Na V 1.2 (encoded by SCN2A), where it was shown to increase sodium current and cause a small negative shift in voltage dependence of activation (19).…”

Section: Figurementioning

confidence: 99%

Sodium channel β1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans

Watanabe¹,

Koopmann²,

Scouarnec³

et al. 2008

J. Clin. Invest.

266

309

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Brugada syndrome is a genetic disease associated with sudden cardiac death that is characterized by ventricular fibrillation and right precordial ST segment elevation on ECG. Loss-of-function mutations in SCN5A, which encodes the predominant cardiac sodium channel α subunit Na V 1.5, can cause Brugada syndrome and cardiac conduction disease. However, SCN5A mutations are not detected in the majority of patients with these syndromes, suggesting that other genes can cause or modify presentation of these disorders. Here, we investigated SCN1B, which encodes the function-modifying sodium channel β1 subunit, in 282 probands with Brugada syndrome and in 44 patients with conduction disease, none of whom had SCN5A mutations. We identified 3 mutations segregating with arrhythmia in 3 kindreds. Two of these mutations were located in a newly described alternately processed transcript, β1B. Both the canonical and alternately processed transcripts were expressed in the human heart and were expressed to a greater degree in Purkinje fibers than in heart muscle, consistent with the clinical presentation of conduction disease. Sodium current was lower when Na V 1.5 was coexpressed with mutant β1 or β1B subunits than when it was coexpressed with WT subunits. These findings implicate SCN1B as a disease gene for human arrhythmia susceptibility.

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Modulation of Nav1.5 by ?1- and ?3-subunit co-expression in mammalian cells

Cited by 65 publications

References 46 publications

Mouse models of SCN5A-related cardiac arrhythmias

Mouse models of SCN5A-related cardiac arrhythmias

Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy

Sodium channel β1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans

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