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

Sudden death caused by disturbances of the cardiac 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 cellular mechanisms underlying these diseases. The general goal of this project is to obtain detailed information about the regulation of one specific ion channel (a membrane protein mediating the flow of ions across the cell membrane) called Nav1.5. This channel is mainly expressed in the heart and mediates the influx of sodium ions into cardiac cells, hence playing a key role in the electrical activity of the heart. Many recent studies have demonstrated that malfunction of this channel caused by genetic mutations may lead to a large number of different cardiac pathologies. In this project, we postulate that this channel is regulated by two types of proteins interacting directly with it: (1) ubiquitin ligases and (2) anchoring proteins. In order to study the physiological relevance of these interactions, we have generated mouse lines that have been genetically modified. Important domains of the mouse gene coding for Nav1.5 have been altered in a way that these proteins will not be able anymore to interact with the channel. We are currently investigating the consequences of these genetic modifications on the electrical activity of the heart. to this end, we are carrying out biochemistry, cellular and whole-animal experiments. The new knowledge that will be obtained by performing the proposed experiments will allow us to understand much more precisely how Nav1.5 is regulated. This will permit us to propose new models about how this channel is involved in arrhythmic diseases and eventually better prevent sudden cardiac death.

Grant Value393804
Commencement Date / Completion Date1 April 2011 - 3 March 2013
Contributors Gabriel Hugues (Principle Investigator)
Funders [4] Swiss National Science Foundation
Keywordsarrhythmias, congenital long QT syndrome, Brugada syndrome, cardiac electrophysiology, sodium channel, ubiquitin, dystrophin
Publications 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. Heart, 9(3), pp. 440-8. London: BMJ Publishing Group 10.1016/j.hrthm.2011.10.026
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. European journal of medicinal chemistry, 46(8), pp. 3486-98. Paris: Elsevier Masson SAS 10.1016/j.ejmech.2011.05.015
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. Annals of noninvasive electrocardiology, 16(2), pp. 213-8. Oxford: Wiley 10.1111/j.1542-474X.2011.00419.x
Albesa, Maxime; Grilo, Liliana Sintra; Gavillet, Bruno; Abriel, Hugues (2011). Nedd4-2-dependent ubiquitylation and regulation of the cardiac potassium channel hERG1. Journal of molecular and cellular cardiology, 51(1), pp. 90-8. Oxford: Elsevier 10.1016/j.yjmcc.2011.03.015
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). European Heart Journal, 32(9), pp. 1077-88. Oxford: Oxford University Press 10.1093/eurheartj/ehr076
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. Neuroscience, 227, pp. 370-380. Oxford: Elsevier 10.1016/j.neuroscience.2012.09.044
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. PLoS ONE, 7(7), e41032. Lawrence, Kans.: Public Library of Science 10.1371/journal.pone.0041032
Suter, Marc R.; Kirschmann, Guylène; Laedermann, Cedric J.; Abriel, Hugues; Decosterd, Isabelle (2012). Rufinamide attenuates mechanical allodynia in a model of neuropathic pain in the mouse and stabilizes voltage-gated sodium channel inactivated state. Anesthesiology, 118(1), pp. 160-172. Hagerstown, Md.: Lippincott Williams & Wilkins 10.1097/ALN.0b013e318278cade
Laedermann, Cédric J; Syam, Ninda; Pertin, Marie; Decosterd, Isabelle; Abriel, Hugues (2013). β1- and β3- voltage-gated sodium channel subunits modulate cell surface expression and glycosylation of Nav1.7 in HEK293 cells. Frontiers in cellular neuroscience, 7, p. 137. Lausanne: Frontiers Research Foundation 10.3389/fncel.2013.00137

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