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Co-regulation of cardiac ion channels: focus on the sodium channel Nav1.5

English title Co-regulation of cardiac ion channels: focus on the sodium channel Nav1.5
Applicant Abriel Hugues
Number 184783
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 01.07.2019 - 30.06.2023
Approved amount 938'879.00
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All Disciplines (2)

Discipline
Cardiovascular Research
Biophysics

Keywords (10)

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

Lay Summary (French)

Lead
Les canaux ioniques sont des protéines qui se trouvent dans la membrane cellulaire de toutes les cellules animales. Une altération de la fonction de ces canaux ioniques, aussi nommée « 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 cœur. 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 projet, nous proposons d'étudier les interactions moléculaires et fonctionnelles entre les canaux Nav1.5 et d’autres canaux exprimés dans les cellules cardiaques. Il s’agit des canaux Nav1.4, Cav1.2 et TRPM4. 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 pour les patients qui souffrent d’arythmies cardiaques.

Direct link to Lay Summary Last update: 29.03.2019

Responsible applicant and co-applicants

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Associated projects

Number Title Start Funding scheme
160620 NCCR TransCure: From transport physiology to identification of therapeutic targets (phase II) 01.11.2014 National Centres of Competence in Research (NCCRs)
165741 Multiple Nav1.5 Pools in Cardiac Cells: Molecular Determinants and Functional Roles 01.04.2016 Project funding (Div. I-III)

Abstract

Background - Numerous human diseases are caused by genetic or acquired dysfunction of ion channels, the so-called channelopathies. Cardiac arrhythmias and conduction disturbances, epilepsies, pain syndromes, periodic paralysis, and cystic fibrosis are among the best-studied channelopathies. Ion channels are membrane proteins allowing the passage of ions. They are essential for a plethora of cellular functions such as transmission of information, muscle cell contraction, and epithelial transport. In cardiac cells, more than 20 ion channels are activated and inactivated in a coordinated way to generate the action potential (AP), propagate the electrical impulse throughout the heart compartments, and induce contraction of the myocytes. Over the past 25 years, more than a thousand mutations in the genes coding for ion channels and their associated proteins have been found to cause cardiac disorders. The congenital long QT syndrome (LQTS) and Brugada syndrome (BrS) can both lead to sudden cardiac arrest and are the best-studied cardiac channelopathies. The Nav1.5 cardiac sodium channel, whose gene is SCN5A, plays a pivotal role in such disorders. Several hundred genetic variants in SCN5A have been found in patients with a broad spectrum of manifestations, such as LQTS type 3, BrS, atrial fibrillation, and dilated cardiomyopathy. This phenotypic diversity suggests that Nav1.5 may have different roles in normal physiology and cardiac disease. One current hypothesis in the field is that this variability in patients carrying SNC5A variants results from different populations (pools) of Nav1.5 channels that are associated with distinct regulatory proteins and are expressed in different membrane compartments of cardiac cells. While many research groups have started to investigate this working hypothesis, limited information is available thus far on the distinct or overlapping functions of these populations of Nav1.5 in cardiomyocytes.Over the past 15 years, our group has significantly contributed to the characterization of proteins interacting with and regulating Nav1.5. In most cases, these interactors are themselves involved in distinct types of cardiac channelopathies. Furthermore, we demonstrated the presence of at least two pools of Nav1.5 channels in cardiac cells. One population of Nav1.5 channels is expressed at cell-to-cell contact domains, the intercalated discs (ID), while another pool is present at the lateral membrane (LM) of the cells. Currently, we are addressing the question of whether this lateral population is constituted of distinct sub-populations. Additional intriguing information regarding the proteins interacting with Nav1.5 has been recently published. While Nav1.5 is a sodium channel by itself, as the pore-forming protein it interacts with other Nav1.5 proteins (alpha-alpha Nav1.5 interaction) or with other ion channels such as the inward rectifier potassium channel Kir2.1. Importantly, this alpha-alpha Nav1.5 interaction seems to be essential for the observed dominant negative effect (DNE) seen with mutant Nav1.5 channels. These recent observations motivate us to further explore the existence, the mechanisms, and the relevance of the interactions of Nav1.5 with itself and other channels in cardiac cells. Specifically, in this project, we plan to investigate the interactions and co-regulation of Nav1.5 and the sodium channel Nav1.4, the calcium channel Cav1.2, and the transient receptor potential channel TRPM4. Working Hypothesis - We postulate that direct interactions of Nav1.5 with another Nav1.5 channel and other types of cardiac channels (Nav1.4, Cav1.2, or TRPM4) regulate Nav1.5 function, its density at the cell membrane, and its targeting to specific membrane domains. Such co-regulatory mechanisms may underlie the overlaps in phenotypes seen in patients carrying mutations in the genes encoding these cardiac channels.In the current proposal, we plan to address the following three specific aims:1. To identify the molecular determinants and relevance of Nav1.5-Nav1.4 and Nav1.5-Nav1.5 interactions 2. To demonstrate the existence and investigate the role of the Nav1.5-Cav1.2 interaction in cardiac cells3. To decipher the mechanisms of co-regulation of Nav1.5 and the TRPM4 channel in cardiac cellsExperimental Design - We propose to investigate Nav1.5 and interacting channels by performing biochemistry, cell and tissue imaging, and physiological experiments using both cellular expression systems and cells and tissues from genetically modified mouse lines that are either already available or that we plan to generate. Expected Value of the Project - During the past 25 years, the channel Nav1.5 has been shown to play a crucial role in a long list of cardiac disorders. However, it is still far from clear how this channel and other cardiac channels are involved in a wide range of pathological cardiac phenotypes. The results of the proposed experiments will shed light on the molecular mechanisms involving channel-channel interactions that may underlie these cardiac channelopathies. We expect that this knowledge will lead to novel therapeutic targets or gene candidates to be investigated in patients with ion-channel-related cardiac disorders.
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