Dataset Information

Diseases caused by mutations in Nav1.5 interacting proteins.

ABSTRACT: Sodium current in the heart flows principally through the pore protein NaV1.5, which is part of a complex of interacting proteins that serve both to target and localize the complex in the membrane, and to modulate function by such post-translational modifications as phosphorylation and nitrosylation. Multiple mutations in seven different NaV1.5 interacting proteins have been associated with dysfunctional sodium current and inherited cardiac diseases, including long QT syndrome, Brugada syndrome, atrial fibrillation, and cardiomyopathy, as well as sudden infant death syndrome (SIDS). Mutations in as yet unidentified interacting proteins may account for cardiac disease for which a genetic basis has not yet been established. Characterizing the mechanisms by which these mutations cause disease may give insight into etiologies and treatments of more common acquired cardiac disease, such as ischemia and heart failure.

SUBMITTER: Kyle JW

PROVIDER: S-EPMC4226528 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Diseases caused by mutations in Nav1.5 interacting proteins.

Kyle John W JW Makielski Jonathan C JC

Cardiac electrophysiology clinics 20141201 4

Sodium current in the heart flows principally through the pore protein NaV1.5, which is part of a complex of interacting proteins that serve both to target and localize the complex in the membrane, and to modulate function by such post-translational modifications as phosphorylation and nitrosylation. Multiple mutations in seven different NaV1.5 interacting proteins have been associated with dysfunctional sodium current and inherited cardiac diseases, including long QT syndr ...[more]

PMID: 25395996

Similar Datasets

Project description:RationaleThe cardiac sodium channel NaV1.5 has a fundamental role in excitability and conduction. Previous studies have shown that sodium channels cluster together in specific cellular subdomains. Their association with intracellular organelles in defined regions of the myocytes, and the functional consequences of that association, remain to be defined.ObjectiveTo characterize a subcellular domain formed by sodium channel clusters in the crest region of the myocytes and the subjacent subsarcolemmal mitochondria.Methods and resultsThrough a combination of imaging approaches including super-resolution microscopy and electron microscopy we identified, in adult cardiac myocytes, a NaV1.5 subpopulation in close proximity to subjacent subsarcolemmal mitochondria; we further found that subjacent subsarcolemmal mitochondria preferentially host the mitochondrial NCLX (Na+/Ca2+ exchanger). This anatomic proximity led us to investigate functional changes in mitochondria resulting from sodium channel activity. Upon TTX (tetrodotoxin) exposure, mitochondria near NaV1.5 channels accumulated more Ca2+ and showed increased reactive oxygen species production when compared with interfibrillar mitochondria. Finally, crosstalk between NaV1.5 channels and mitochondria was analyzed at a transcriptional level. We found that SCN5A (encoding NaV1.5) and SLC8B1 (which encode NaV1.5 and NCLX, respectively) are negatively correlated both in a human transcriptome data set (Genotype-Tissue Expression) and in human-induced pluripotent stem cell-derived cardiac myocytes deficient in SCN5A.ConclusionsWe describe an anatomic hub (a couplon) formed by sodium channel clusters and subjacent subsarcolemmal mitochondria. Preferential localization of NCLX to this domain allows for functional coupling where the extrusion of Ca2+ from the mitochondria is powered, at least in part, by the entry of sodium through NaV1.5 channels. These results provide a novel entry-point into a mechanistic understanding of the intersection between electrical and structural functions of the heart.

Dataset Information

Diseases caused by mutations in Nav1.5 interacting proteins.

Publications

Diseases caused by mutations in Na<sub>v</sub>1.5 interacting proteins.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets