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Multiple Nav1.5 Pools in Cardiac Cells: Molecular Determinants and Functional Roles

English title Multiple Nav1.5 Pools in Cardiac Cells: Molecular Determinants and Functional Roles
Applicant Abriel Hugues
Number 165741
Funding scheme Project funding (Div. I-III)
Research institution Institute of Biochemistry and Molecular Medicine (IBMM) Universität Bern
Institution of higher education University of Berne - BE
Main discipline Cardiovascular Research
Start/End 01.04.2016 - 30.06.2019
Approved amount 756'000.00
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Keywords (9)

voltage-gated sodium channel; Brugada syndrome; ion channels; arrhythmias; cardiac cells; cardiac conduction; cardiac electrophysiology; congenital long QT syndrome; medical genetics

Lay Summary (French)

Lead
Les canaux ioniques sont de protéines qui se trouvent dans la membrane cellulaire de toutes les cellules animales. Une altération de la fonction de ces canaux ioniques, aussi nommé « canalopathie », peut conduire à diverses maladies telles qu’épilepsies, migraines, paralysies, hypertension et hypotension artérielle, et mucoviscidose.
Lay summary

Notre projet a pour objectif d’étudier les mécanismes de régulation du canal sodique dépendant du voltage nommé Nav1.5 qui se trouve dans les cellules du coeur. Lors de nos précédentes études, nous avons pu démontrer que le gène de ce canal est fréquemment muté et dysfonctionnel chez des patients et familles qui souffrent de troubles du rythme cardiaque (arythmies du cœur). Cependant, un grand nombre de détails nous manquent pour une bonne compréhension des rôles de ce canal Nav1.5 dans les cellules cardiaques. Dans ce nouveua projet, nous allons étudier les mécanismes moléculaires et cellulaires qui permettent une localisation précise dans les différentes parties de la membrane cellulaire des cellules cardiaques. Nous estimons que ces résultats nous permettrons de mieux comprendre les conséquences des malfonctions du canal Nav1.5 et permettront d’élaborer de nouvelles stratégies de traitements des patients qui souffrent d’arythmies cardiaques.

Direct link to Lay Summary Last update: 25.03.2016

Responsible applicant and co-applicants

Employees

Publications

Associated projects

Number Title Start Funding scheme
172237 Elucidating differential regulation of the cardiac sodium channel Nav1.5 by super-resolution microscopy 01.02.2017 Doc.Mobility
184783 Co-regulation of cardiac ion channels: focus on the sodium channel Nav1.5 01.07.2019 Project funding (Div. I-III)
147060 Molecular Determinants of Nav1.5 Multiprotein Complexes in Cardiac Cells 01.04.2013 Project funding (Div. I-III)

Abstract

Background - Ion channels are membrane proteins that are essential for numerous cellular functions. Many human disorders such as cardiac arrhythmias, pain syndromes, migraine, and hereditary hypertension are caused by either genetic or acquired dysfunction of ion channels, so-called channelopathies. In cardiac cells (cardiomyocytes) many ion channels play key roles in the excitation-contraction process as well as in electrical impulse propagation. In the past years, the molecular identity of most ionic currents that are involved in the generation of the cardiac action potential (AP) have been deciphered. In addition, hundreds of mutations have been described in the genes coding for cardiac ion channels or proteins interacting with ion channels in patients with heart disorders. Among the many open questions in the field of cardiac genetic channelopathies, one should note the fact that for a given gene, for example SCN5A coding for the cardiac sodium channel Nav1.5, there is an unexpectedly high phenotypic diversity. Mutations in SCN5A have been found in patients and families with various inherited arrhythmic disorders such as congenital long QT syndrome (LQTS), Brugada syndrome, conduction slowing, sinusal disorders, dilated cardiomyopathies, atrial fibrillation, and exercise-induced tachycardia. This list of pathologies underlines the importance of Nav1.5 in human physiology and pathophysiology. The molecular determinants of the cell biology and regulation of Nav1.5 is an active field of research, since it is postulated that the mentioned phenotypic diversity may result from different populations (pools) of Nav1.5 channels, located in different membrane compartments of the cardiomyocytes. These distinct Nav1.5 pools may have different functions and may be differentially regulated. Thus far, however, there is only limited knowledge about the specific functions of these pools of Nav1.5 channels in cardiomyocytes.The current proposal is a continuation of our research program, initiated more than a decade ago, in which our group has characterized proteins that interact with and regulate Nav1.5, and demonstrated the presence of at least two pools of Nav1.5 channels in cardiac cells. It has been shown that many Nav1.5 channels are expressed at the intercalated discs (domains of cell-to-cell contact), while another pool of Nav1.5 is present at the lateral membrane of the cells and mainly interacts with the dystrophin multi-protein complex. Important for the translational aspect of this research, several of the Nav1.5 interacting proteins that we described in the past, such as alpha1-syntrophin and SAP97, have been found to be mutated in patients with genetic arrhythmic disorders.Working Hypothesis - We postulate that at least three pools of Nav1.5 channels are located at (1) the intercalated discs, (2) the extra-tubular lateral membrane, and (3) the t-tubular systems. Distinct interacting proteins may form specific macro-molecular complexes in these three membrane domains. These protein complexes may serve to either target and anchor Nav1.5 channels to the specific domain and/or adapt signaling proteins. Furthermore, we hypothesize that correct biosynthesis and trafficking of Nav1.5 may depend on alpha-alpha subunit interactions for which the molecular determinants are still unknown.In the current proposal, we plan to address the following three specific aims:1. To demonstrate the in vivo function of cardiac alpha1-syntrophin and its roles in arrhythmias 2. To decipher the role of the double MAGUK complex SAP97/CASK in regulating Nav1.53. To identify the molecular determinants and relevance of Nav1.5 alpha-alpha subunit interactionsExperimental Design - We propose to investigate Nav1.5 at the molecular and functional level mainly by using cardiomyocytes from genetically-modified mice. These mouse lines are currently available in our group. In vivo, cellular and biochemical phenotyping of these mice will be performed, using a set of techniques available in our laboratory and in collaborating groups as stated in the proposal.Expected Value of the Project - Human genetic findings of the past 20 years demonstrated that Nav1.5 plays a crucial role in cardiac pathology. Furthermore, several of the genes and proteins that have been found to regulate Nav1.5 were also shown to be either mutated or dysregulated in different types of arrhythmias and other cardiac pathological manifestations. By continuing the investigation of the regulatory mechanisms and associated proteins, and in particular, the deciphering of the molecular determinants of the distinct Nav1.5 pools, this will lead to novel genes/targets to be investigated in patients with Nav1.5-dependent cardiac disorders.
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