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In vivo relevance of the PY and PDZ-domain binding motifs of the cardiac sodium channel Nav1.5

English title In vivo relevance of the PY and PDZ-domain binding motifs of the cardiac sodium channel Nav1.5
Applicant Abriel Hugues
Number 135693
Funding scheme Project funding (Div. I-III)
Research institution Department for BioMedical Research Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Cardiovascular Research
Start/End 01.04.2011 - 31.03.2013
Approved amount 393'804.00
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Keywords (7)

arrhythmias; congenital long QT syndrome; Brugada syndrome; cardiac electrophysiology; sodium channel; ubiquitin; dystrophin

Lay Summary (English)

Lead
Lay summary
Sudden death caused by disturbances of thecardiac rhythm (arrhythmias) is a common cause of death in industrialized countries.The mechanisms underlying cardiac arrhythmias are complex and dynamic.Thus far, we only partially understand the molecular and cellularmechanisms underlying these diseases.The general goal of this project is to obtain detailed information aboutthe regulation of one specific ion channel (a membrane protein mediatingthe flow of ions across the cell membrane) called Nav1.5. This channelis mainly expressed in the heart and mediates the influx of sodium ionsinto cardiac cells, hence playing a key role in the electricalactivity of the heart. Many recent studies have demonstrated thatmalfunction of this channel caused by genetic mutations may lead to alarge number of different cardiac pathologies.In this project, we postulate that this channel is regulated by twotypes of proteins interacting directly with it: (1) ubiquitin ligasesand (2) anchoring proteins.In order to study the physiological relevance of these interactions, we have generated mouse lines that have been geneticallymodified. Important domains of the mouse gene coding for Nav1.5 have been alteredin a way that these proteins will not be able anymore to interact with thechannel. We are currently investigating the consequences ofthese genetic modifications on the electrical activity of the heart. to this end, we are carrying out biochemistry, cellular andwhole-animal experiments.The new knowledge that will be obtained by performing the proposedexperiments will allow us to understand much more precisely how Nav1.5is regulated. This will permit us to propose new models about how thischannel is involved in arrhythmic diseases and eventually better preventsudden cardiac death.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Biochemical, single-channel, whole-cell patch clamp, and pharmacological analyses of endogenous TRPM4 channels in HEK293 cells.
Amarouch Mohamed-Yassine, Syam Ninda, Abriel Hugues (2013), Biochemical, single-channel, whole-cell patch clamp, and pharmacological analyses of endogenous TRPM4 channels in HEK293 cells., in Neuroscience letters, 541, 105-10.
Molecular genetics and functional anomalies in a series of 248 Brugada cases with 11 mutations in the TRPM4 channel.
Liu Hui, Chatel Stéphanie, Simard Christophe, Syam Ninda, Salle Laurent, Probst Vincent, Morel Julie, Millat Gilles, Lopez Michel, Abriel Hugues, Schott Jean-Jacques, Guinamard Romain, Bouvagnet Patrice (2013), Molecular genetics and functional anomalies in a series of 248 Brugada cases with 11 mutations in the TRPM4 channel., in PloS one, 8(1), 54131-54131.
Proteasome inhibitor (MG132) rescues Nav1.5 protein content and the cardiac sodium current in dystrophin-deficient mdx (5cv) mice.
Rougier Jean-Sébastien, Gavillet Bruno, Abriel Hugues (2013), Proteasome inhibitor (MG132) rescues Nav1.5 protein content and the cardiac sodium current in dystrophin-deficient mdx (5cv) mice., in Frontiers in physiology, 4, 51-51.
Rufinamide attenuates mechanical allodynia in a model of neuropathic pain in the mouse and stabilizes voltage-gated sodium channel inactivated state.
Suter Marc R, Kirschmann Guylène, Laedermann Cedric J, Abriel Hugues, Decosterd Isabelle (2013), Rufinamide attenuates mechanical allodynia in a model of neuropathic pain in the mouse and stabilizes voltage-gated sodium channel inactivated state., in Anesthesiology, 118(1), 160-72.
Deubiquitylating enzyme USP2 counteracts Nedd4-2-mediated downregulation of KCNQ1 potassium channels.
Krzystanek Katarzyna, Rasmussen Hanne Borger, Grunnet Morten, Staub Olivier, Olesen Søren-Peter, Abriel Hugues, Jespersen Thomas (2012), Deubiquitylating enzyme USP2 counteracts Nedd4-2-mediated downregulation of KCNQ1 potassium channels., in Heart rhythm : the official journal of the Heart Rhythm Society, 9(3), 440-8.
Mapping genetic variants associated with beta-adrenergic responses in inbred mice.
Hersch Micha, Peter Bastian, Kang Hyun Min, Schüpfer Fanny, Abriel Hugues, Pedrazzini Thierry, Eskin Eleazar, Beckmann Jacques S, Bergmann Sven, Maurer Fabienne (2012), Mapping genetic variants associated with beta-adrenergic responses in inbred mice., in PloS one, 7(7), 41032-41032.
Neuronal expression of the ubiquitin ligase Nedd4-2 in rat dorsal root ganglia: modulation in the spared nerve injury model of neuropathic pain.
Cachemaille M, Laedermann C J, Pertin M, Abriel H, Gosselin R-D, Decosterd I (2012), Neuronal expression of the ubiquitin ligase Nedd4-2 in rat dorsal root ganglia: modulation in the spared nerve injury model of neuropathic pain., in Neuroscience, 227, 370-80.
Block of the hERG channel by bupivacaine: Electrophysiological and modeling insights towards stereochemical optimization.
Sintra Grilo Liliana, Carrupt Pierre-Alain, Abriel Hugues, Daina Antoine (2011), Block of the hERG channel by bupivacaine: Electrophysiological and modeling insights towards stereochemical optimization., in European journal of medicinal chemistry, 46(8), 3486-98.
Identification of a novel loss-of-function calcium channel gene mutation in short QT syndrome (SQTS6).
Templin Christian, Ghadri Jelena-Rima, Rougier Jean-Sébastien, Baumer Alessandra, Kaplan Vladimir, Albesa Maxime, Sticht Heinrich, Rauch Anita, Puleo Colleen, Hu Dan, Barajas-Martinez Héctor, Antzelevitch Charles, Lüscher Thomas F, Abriel Hugues, Duru Firat (2011), Identification of a novel loss-of-function calcium channel gene mutation in short QT syndrome (SQTS6)., in European heart journal, 32(9), 1077-88.
Nedd4-2-dependent ubiquitylation and regulation of the cardiac potassium channel hERG1.
Albesa Maxime, Grilo Liliana Sintra, Gavillet Bruno, Abriel Hugues (2011), Nedd4-2-dependent ubiquitylation and regulation of the cardiac potassium channel hERG1., in Journal of molecular and cellular cardiology, 51(1), 90-8.
Patient with syncope and LQTS carrying a mutation in the PAS domain of the hERG1 channel.
Grilo Liliana Sintra, Schläpfer Jürg, Fellmann Florence, Abriel Hugues (2011), Patient with syncope and LQTS carrying a mutation in the PAS domain of the hERG1 channel., in Annals of noninvasive electrocardiology : the official journal of the International Society for Holt, 16(2), 213-8.

Associated projects

Number Title Start Funding scheme
112552 Pharmacogenetic analysis of the cardiovascular response in mice 01.05.2006 Project funding (Div. I-III)
139231 Advancement of functional genomics research at the University of Bern by extension of LC-MS platform 01.07.2012 R'EQUIP
120707 In vivo relevance of the PY and PDZ-domain binding motifs of the cardiac sodium channel Nav1.5 01.04.2008 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

BOE, see the 3-page project attached.
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