The cardiac sodium channel H558R variant improves survival in heart failure

Aleong, Ryan G.; Shah, A.; Michalec, Michael; Bedi, M.; McNamara, Dennis M.; London, Barry; Murali, Srinivas; Cadaret, Linda; Mathier, Michael A.; McGowan, G. K.

doi:10.1016/j.hrthm.2005.02.324

Cited by 2 publications

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“…This polymorphism is long known to be a genetic modifier of cardiac pathologies. Indeed, H558R can promote the functionality of mutated channels found in BrS, Long QT Syndrome and was also clinically observed to improve the survival of HF patients (Shinlapawittayatorn et al, 2011b;Aleong et al, 2005;Poelzing et al, 2006;Viswanathan et al, 2003;Marangoni et al, 2011;Matsumura et al, 2017). We therefore asked if the Na v 1.5-H558R polymorphism could improve the survival of HF patients by also impairing the DN-effect caused by the HF splice variant Na v 1.5-G1642X.…”

Section: Na V 15-g1642x Does Not Exert a Dominant-negative Effect Onmentioning

confidence: 99%

“…Our team previously found that the common Na v 1.5-H558R can interact with multiple pathogenic SCN5A genetic mutations found in BrS or Long QT syndrome to rescue their pathogenic effect ( Ye et al, 2003 ; Shinlapawittayatorn et al,2011a,b ). Interestingly, this Na v 1.5-H558R polymorphism was reported to improve the survival of HF patients ( Aleong et al, 2005 ). We therefore also explored if the presence of this polymorphism could influence the DN-effect produced by the splice variant.…”

Section: Introductionmentioning

confidence: 99%

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A Heart Failure-Associated SCN5A Splice Variant Leads to a Reduction in Sodium Current Through Coupled-Gating With the Wild-Type Channel

et al. 2021

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Nav1.5, encoded by the gene SCN5A, is the predominant voltage-gated sodium channel expressed in the heart. It initiates the cardiac action potential and thus is crucial for normal heart rhythm and function. Dysfunctions in Nav1.5 have been involved in multiple congenital or acquired cardiac pathological conditions such as Brugada syndrome (BrS), Long QT Syndrome Type 3, and heart failure (HF), all of which can lead to sudden cardiac death (SCD) – one of the leading causes of death worldwide. Our lab has previously reported that Nav1.5 forms dimer channels with coupled gating. We also found that Nav1.5 BrS mutants can exert a dominant-negative (DN) effect and impair the function of wildtype (WT) channels through coupled-gating with the WT. It was previously reported that reduction in cardiac sodium currents (INa), observed in HF, could be due to the increased expression of an SCN5A splice variant – E28D, which results in a truncated sodium channel (Nav1.5-G1642X). In this study, we hypothesized that this SCN5A splice variant leads to INa reduction in HF through biophysical coupling with the WT. We showed that Nav1.5-G1642X is a non-functional channel but can interact with the WT, resulting in a DN effect on the WT channel. We found that both WT and the truncated channel Nav1.5-G1642X traffic at the cell surface, suggesting biophysical coupling. Indeed, we found that the DN effect can be abolished by difopein, an inhibitor of the biophysical coupling. Interestingly, the sodium channel polymorphism H558R, which has beneficial effect in HF patients, could also block the DN effect. In summary, the HF-associated splice variant Nav1.5-G1642X suppresses sodium currents in heart failure patients through a mechanism involving coupled-gating with the wildtype sodium channel.

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Section: Na V 15-g1642x Does Not Exert a Dominant-negative Effect Onmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Heart Failure-Associated SCN5A Splice Variant Leads to a Reduction in Sodium Current Through Coupled-Gating With the Wild-Type Channel

et al. 2021

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“…One of these, H558R, has an allelic frequency of ∼30%, and in conjunction with the splice variant Q1077 generated continuously in every human heart, 3 the I Na density is dramatically reduced. Recently, this very common polymorphism has been linked to survival status in a registry of acquired cardiomyopathy 45 . It is interesting to speculate that altered Na loading may play a role in both the effect of this common polymorphism, and with the Na channel mutations in familial cardiomyopathy.…”

Section: Na Current Function and Effects On Na Loadingmentioning

confidence: 99%

“…Recently, this very common polymorphism has been linked to survival status in a registry of acquired cardiomyopathy. 45 It is interesting to speculate that altered Na loading may play a role in both the effect of this common polymorphism, and with the Na channel mutations in familial cardiomyopathy.…”

Section: Na Current Function and Effects On Na Loadingmentioning

confidence: 99%

Na⁺ Current in Human Ventricle: Implications for Sodium Loading and Homeostasis

Makielski

Farley

2006

Cardiovasc electrophysiol

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The Na current (I(Na)) in human ventricle is carried through a specific isoform of the voltage gated Na channel in heart. The pore forming alpha-subunit is encoded by the gene SCN5A. Up to four beta-subunits may be associated, and the larger macromolecular complex may include attachments to cytoskeleton and scaffolding proteins, all of which may affect the gating kinetics of the current. I(Na) underlies initiation and propagation of action potentials in the heart and plays a prominent role in cardiac electrophysiology and arrhythmia. In addition, I(Na) also loads the ventricular cell with Na(+) ions and plays an important role in intracellular Na homeostasis. This review considers the structure and function of the human cardiac Na channel that carries I(Na) with a particular consideration of the implications of alterations in I(Na) in acquired cardiac diseases such as hypertrophy, failure, and ischemia, which affect Na loading.

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The cardiac sodium channel H558R variant improves survival in heart failure

Cited by 2 publications

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A Heart Failure-Associated SCN5A Splice Variant Leads to a Reduction in Sodium Current Through Coupled-Gating With the Wild-Type Channel

A Heart Failure-Associated SCN5A Splice Variant Leads to a Reduction in Sodium Current Through Coupled-Gating With the Wild-Type Channel

Na⁺ Current in Human Ventricle: Implications for Sodium Loading and Homeostasis

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The cardiac sodium channel H558R variant improves survival in heart failure

Cited by 2 publications

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A Heart Failure-Associated SCN5A Splice Variant Leads to a Reduction in Sodium Current Through Coupled-Gating With the Wild-Type Channel

A Heart Failure-Associated SCN5A Splice Variant Leads to a Reduction in Sodium Current Through Coupled-Gating With the Wild-Type Channel

Na+ Current in Human Ventricle: Implications for Sodium Loading and Homeostasis

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Na⁺ Current in Human Ventricle: Implications for Sodium Loading and Homeostasis