A5002278517- Cardiac electrophysiology and arrhythmias
- Ion channel regulation and function
- Ion Channels and Receptors
- Receptor Mechanisms and Signaling
- Neuroscience and Neural Engineering
- Neuroscience and Neuropharmacology Research
- Mitochondrial Function and Pathology
- Cardiomyopathy and Myosin Studies
- Cardiovascular Effects of Exercise
- Cardiac pacing and defibrillation studies
- Pain Mechanisms and Treatments
- Ion Transport and Channel Regulation
- Cardiac Arrhythmias and Treatments
- Ubiquitin and proteasome pathways
- ATP Synthase and ATPases Research
- Muscle Physiology and Disorders
- ECG Monitoring and Analysis
- Electrochemical Analysis and Applications
- Healthcare Systems and Practices
- Phytochemicals and Antioxidant Activities
- RNA and protein synthesis mechanisms
- Anesthesia and Neurotoxicity Research
- Adipose Tissue and Metabolism
- Neurobiology and Insect Physiology Research
- Genetic Neurodegenerative Diseases
University of Bern
2016-2025
University of Kinshasa
2021
Inserm
2004-2016
Sorbonne Université
2009-2016
Assistance Publique – Hôpitaux de Paris
2012-2016
University of Michigan
2001-2015
Spanish National Centre for Cardiovascular Research
2015
University of Lausanne
1999-2014
Netherlands Heart Institute
2014
Amsterdam UMC Location University of Amsterdam
2014
The cardiac sodium channel Na(v)1.5 plays a key role in excitability and conduction. 3 last residues of (Ser-Ile-Val) constitute PDZ-domain binding motif that interacts with the syntrophin-dystrophin complex. As dystrophin is absent at intercalated discs, could potentially interact other, yet unknown, proteins this site.The aim study was to determine whether part distinct regulatory complexes lateral membranes discs.Immunostaining experiments demonstrated localizes cardiomyocytes syntrophin....
Liddle's syndrome is an inherited form of hypertension linked to mutations in the epithelial Na+ channel (ENaC). ENaC composed three subunits (α, β, γ), each containing a COOH-terminal PY motif (xPPxY). Mutations causing alter or delete motifs β- γ-ENaC. We recently demonstrated that ubiquitin–protein ligase Nedd4 binds these and regulated by ubiquitination. Here, we investigate, using Xenopus oocyte system, whether affects function. Overexpression wild-type Nedd4, together with ENaC,...
Methadone inhibits the cardiac potassium channel hERG and can cause a prolonged QT interval. is chiral but its therapeutic activity mainly due to (R)-methadone. Whole-cell patch-clamp experiments using cells expressing showed that (S)-methadone blocked current 3.5-fold more potently than (R)-methadone (IC50s (half-maximal inhibitory concentrations) at 37°C: 2 7 μM). As CYP2B6 slow metabolizer (SM) status results in reduced ability metabolize (S)-methadone, electrocardiograms, genotypes, (R)-...
The cardiac sodium channel Na(v)1.5 plays a key role in excitability and conduction. purpose of this study was to elucidate the PDZ domain-binding motif formed by last three residues (Ser-Ile-Val) C-terminus. Pull-down experiments were performed using C-terminus fusion proteins human or mouse heart protein extracts, combined with mass spectrometry analysis. These revealed that associates dystrophin, interaction mediated alpha- beta-syntrophin proteins. Truncation abolished interaction. We...
Sodium channels isolated from mammalian brain are composed of alpha-, beta(1)-, and beta(2)-subunits. The composition sodium in cardiac muscle, however, has not been defined, disagreement exists over which beta-subunits expressed the myocytes. Some investigators have demonstrated beta(1) expression heart. Others detected any auxiliary subunits. On basis Northern blot analysis total RNA, beta(2) thought to be exclusive neurons absent muscle.The goal this study was define subunit We show that...
Na v 1.5, the cardiac isoform of voltage-gated + channel, is critical to heart excitability and conduction. However, mechanisms regulating its expression at cell membrane are poorly understood. The 1.5 C-terminus contains a PY-motif (xPPxY) that known act as binding site for Nedd4/Nedd4-like ubiquitin-protein ligases. Because Nedd4-2 well expressed in heart, we investigated role ubiquitination regulation 1.5. Yeast two-hybrid GST-pulldown experiments revealed an interaction between Nedd4-2,...
Defects of the SCN5A gene encoding cardiac sodium channel α-subunit are associated with both long QT-3 (LQT-3) subtype long-QT syndrome and Brugada (BrS). One previously described mutation (1795insD) in C terminus results a clinical phenotype combining QT prolongation ST segment elevation, indicating close interrelationship between two disorders. Here we provide additional evidence that these disorders closely related. We report analysis novel mutations on same codon, Y1795C Y1795H (BrS),...
Short QT syndrome (SQTS) is a genetically determined ion-channel disorder, which may cause malignant tachyarrhythmias and sudden cardiac death. Thus far, mutations in five different genes encoding potassium calcium channel subunits have been reported. We present, for the first time, novel loss-of-function mutation coding an L-type subunit. The electrocardiogram of affected member single family revealed interval 317 ms (QTc 329 ms) with tall, narrow, symmetrical T-waves. Invasive...
Brugada syndrome (BrS) is characterized by ventricular tachyarrhythmias leading to sudden cardiac death and caused, in part, mutations the SCN5A gene encoding sodium channel Na(v)1.5. Fever can trigger or exacerbate clinical manifestations of BrS. The aim this work was characterize genetic molecular determinants fever-dependent BrS.Four male patients with typical BrS ST-segment elevation V1-V3 arrhythmias during fever were screened for gene. Wild-type (WT) mutant Na(v)1.5 channels expressed...
Brugada syndrome (BrS) is a condition defined by ST-segment alteration in right precordial leads and risk of sudden death. Because BrS often associated with bundle branch block the TRPM4 gene involved conduction blocks, we screened for anomalies cases. The DNA 248 cases no SCN5A mutations were mutations. Among this cohort, 20 patients had 11 Two previously cardiac blocks 9 new (5 absent from ∼14′000 control alleles 4 statistically more prevalent cohort than alleles). In addition to Brugada,...
Peripheral neuropathic pain is a disabling condition resulting from nerve injury. It characterized by the dysregulation of voltage-gated sodium channels (Navs) expressed in dorsal root ganglion (DRG) sensory neurons. The mechanisms underlying altered expression Na(v)s remain unknown. This study investigated role E3 ubiquitin ligase NEDD4-2, which known to ubiquitylate Navs, pathogenesis mice. spared injury (SNI) model traumatic injury-induced was used, and an Na(v)1.7-specific inhibitor,...
Background— Sodium channel Na V 1.5 underlies cardiac excitability and conduction. The last 3 residues of (Ser-Ile-Val) constitute a PDZ domain–binding motif that interacts with proteins such as syntrophins SAP97 at different locations within the cardiomyocyte, thus defining distinct pools multiprotein complexes. Here, we explored in vivo clinical impact this through characterization mutant mice genetic screening patients. Methods Results— To investigate regulatory role motif, generated...
Abstract Transient receptor potential (TRP) melastatin 4 (TRPM4) protein is a calcium-activated monovalent cation channel associated with various genetic and cardiovascular disorders. The anthranilic acid derivative NBA potent specific TRPM4 inhibitor, but its binding site in has been unknown, although this information crucial for drug development targeting TRPM4. We determine three cryo-EM structures of full-length human embedded native lipid nanodiscs without bound to NBA, an derivative,...
One of the most exciting recent developments in field retroviruses is finding that their Gag proteins hijack cellular from mutivesicular body (MVB) pathway during budding process. The oncoretroviruses possess a PPxY motif recruits ubiquitin ligase Nedd4 family, whereas those human immunodeficiency virus interact through PTAP with Tsg101, protein ESCRT-1 complex. It currently assumed and Tsg101 represent equivalent entry gates towards same process leading to budding, both partners are...
Objective: The voltage-gated KCNQ1 potassium channel regulates key physiological functions in a number of tissues. In the heart, α-subunits assemble with KCNE1 β-subunits forming complex constituting delayed rectifier current IKs. epithelia, channels participate controlling body electrolyte homeostasis. Several regulatory mechanisms complexes have been reported, including protein kinase A (PKA)-phosphorylation and β-subunit interactions. However, membrane density attracted less attention.
The voltage-gated Na + channels (Na v ) form a family composed of 10 genes. COOH termini contain cluster amino acids that are nearly identical among 7 the members. This COOH-terminal sequence, PPSYDSV, is PY motif known to bind WW domains E3 protein-ubiquitin ligases Nedd4 family. We recently reported cardiac 1.5 regulated by Nedd4-2. In this study, we further investigated molecular determinants regulation proteins. When expressed in HEK-293 cells and studied using whole cell voltage...