ArticleCardiovascular research2016
Nav1.5 N-terminal domain binding to α1-syntrophin increases membrane density of human Kir2.1, Kir2.2 and Nav1.5 channels.
Article in Cardiovascular research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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54 citing papers in PubMed, 91 citations in OpenAlex.
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- Molecular stratification of arrhythmogenic mechanisms in the Andersen Tawil syndrome.Cardiovascular research · 2023Article
- Identification of Dp140 and α1-syntrophin as novel molecular interactors of the neuronal CaPflugers Archiv : European journal of physiology · 2023Article
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- A Novel DLG1 Variant in a Family with Brugada Syndrome: Clinical Characteristics and In Silico Analysis.Genes · 2023Article
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- Cardiac-targeted PIASy gene silencing mediates deSUMOylation of caveolin-3 and prevents ischemia/reperfusion-induced NaMilitary Medical Research · 2022Article
- Kir2.1 dysfunction at the sarcolemma and the sarcoplasmic reticulum causes arrhythmias in a mouse model of Andersen-Tawil syndrome type 1.Nature cardiovascular research · 2022Article
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
Abstract
aimsCardiac excitability and refractoriness are largely determined by the function and number of inward rectifier K⁺ channels (Kir2.1-2.3), which are differentially expressed in the atria and ventricles, and Nav1.5 channels. We have focused on how Nav1.5 and Kir2.x function within a macromolecular complex by elucidating the molecular determinants that govern Nav1.5/Kir2.x reciprocal modulation. METHODS AND
resultsThe results demonstrate that there is an unexpected 'internal' PDZ-like binding domain located at the N-terminus of the Nav1.5 channel that mediates its binding to α1-syntrophin. Nav1.5 N-terminal domain, by itself (the 132 aa peptide) (Nter), exerts a 'chaperone-like' effect that increases sodium (I(Na)) and inward rectifier potassium (I(K1)) currents by enhancing the expression of Nav1.5, Kir2.1, and Kir2.2 channels as demonstrated in Chinese hamster ovary (CHO) cells and in rat cardiomyocytes. Site-directed mutagenesis analysis demonstrates that the Nter chaperone-like effect is determined by Serine 20. Nav1.5-Kir2.x reciprocal positive interactions depend on a specific C-terminal PDZ-binding domain sequence (SEI), which is present in Kir2.1 and Kir2.2 channels but not in Kir2.3. Therefore, in human atrial myocytes, the presence of Kir2.3 isoforms precludes reciprocal I(K1)-INa density modulation. Moreover, results in rat and human atrial myocytes demonstrate that binding to α1-syntrophin is necessary for the Nav1.5-Kir2.x-positive reciprocal modulation.
conclusionsThe results demonstrate the critical role of the N-terminal domain of Nav1.5 channels in Nav1.5-Kir2.x-reciprocal interactions and suggest that the molecular mechanisms controlling atrial and ventricular cellular excitability may be different.
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