The role of Calmodulin Kinase in heart rate adaptation and arrhythmias  Page description

Help  Print 
Back »
 

Details of project

  
Identifier
101196
Type K
Principal investigator Bányász, Tamás
Title in Hungarian A kalmodulin kináz szerepének vizsgálata a szívfrekvencia adaptációjában és ritmuszavarokban
Title in English The role of Calmodulin Kinase in heart rate adaptation and arrhythmias
Keywords in Hungarian Kalmodulin kináz, szív, frekvencia adaptáció, aritmiák
Keywords in English Calmodulin kinase, heart, heart rate adaptation, arrhythmia
Discipline
Biophysics (e.g. transport mechanisms, bioenergetics, fluorescence) (Council of Medical and Biological Sciences)50 %
Ortelius classification: Physiological biophysics
Analysis, modelling and simulation of biological systems (Council of Medical and Biological Sciences)40 %
Cell biology and molecular transport mechanisms (Council of Medical and Biological Sciences)10 %
Panel Physiology, Pathophysiology, Pharmacology and Endocrinology
Department or equivalent Department of Physiology (University of Debrecen)
Participants Harmati, Gábor
Horváth, Balázs
Kistamás, Kornél
Nánási, Péter Pál
Szepesy, Judit
Varga, Richárd Sándor
Starting date 2012-03-01
Closing date 2016-10-31
Funding (in million HUF) 16.623
FTE (full time equivalent) 18.08
state closed project
Summary in Hungarian
Cardiac arrhythmias are a leading cause of morbidity and mortality in the western world. Yet, pharmacological approaches to treat arrhythmias have met with only limited success in the past decades, in large part due to incomplete understanding of the cellular and molecular mechanisms of arrhythmias. The proposed work seeks to test the hypothesis that the delayed adaptation of Ca2+ -calmodulin dependent protein kinase II (CaMKII) activity to a sudden change in heart rate can cause imbalanced timing of multiple channels and transporters, which creates a sensitive/vulnerable period when arrhythmias are more likely to develop.
Cardiac electric activity is governed by concerted activity of more than a dozen individual ionic channels. When timing and kinetics are normal, the myocardium generates a regular action potential to initiate muscle contraction resulting in a physiologic heartbeat. Mistiming or abnormal kinetics of ion channels leads to premature heartbeats and arrhythmias. Recently, we have developed an innovative AP-clamp Sequential Dissection technique that gives us unprecedented ability to directly record multiple currents in a single cardiac myocyte during the cell’s own AP with Ca2+ cycling. We will achieve three specific aims in this project: (1) determine how heart rate influences CaMKII activity; (2) determine how CaMKII activity influences the frequency adaptation of ionic currents, AP parameters and occurrence of premature heartbeats in normal and arrhythmic (diseased) hearts; and (3) incorporate experimental data into mathematical models. Taken together, the proposed work will yield new information on the cellular mechanisms of cardiac arrhythmias and provide novel experimental methods and computational tools for designing anti-arrhythmia drug therapies.
Summary
Cardiac arrhythmias are a leading cause of morbidity and mortality in the western world. Yet, pharmacological approaches to treat arrhythmias have met with only limited success in the past decades, in large part due to incomplete understanding of the cellular and molecular mechanisms of arrhythmias. The proposed work seeks to test the hypothesis that the delayed adaptation of Ca2+ -calmodulin dependent protein kinase II (CaMKII) activity to a sudden change in heart rate can cause imbalanced timing of multiple channels and transporters, which creates a sensitive/vulnerable period when arrhythmias are more likely to develop.
Cardiac electric activity is governed by concerted activity of more than a dozen individual ionic channels. When timing and kinetics are normal, the myocardium generates a regular action potential to initiate muscle contraction resulting in a physiologic heartbeat. Mistiming or abnormal kinetics of ion channels leads to premature heartbeats and arrhythmias. Recently, we have developed an innovative AP-clamp Sequential Dissection technique that gives us unprecedented ability to directly record multiple currents in a single cardiac myocyte during the cell’s own AP with Ca2+ cycling. We will achieve three specific aims in this project: (1) determine how heart rate influences CaMKII activity; (2) determine how CaMKII activity influences the frequency adaptation of ionic currents, AP parameters and occurrence of premature heartbeats in normal and arrhythmic (diseased) hearts; and (3) incorporate experimental data into mathematical models. Taken together, the proposed work will yield new information on the cellular mechanisms of cardiac arrhythmias and provide novel experimental methods and computational tools for designing anti-arrhythmia drug therapies.




 

Final report

  
Results in Hungarian
A projekt központi kérdése az volt, hogy a CaMKII hogyan szabályozza a szív ioncsatornáinak működését és ez miként hat az akciós potenciál frekvencia válaszára és rövidtávú variabilitására. A program keretein belül az alábbi eredmények születtek: - Szívelégtelen nyúl modellben az emelkedett CaMKII aktivitás hatására fokozódik a nátrium áram és a nátrium-kalcium cseremechanizmus intenzitása. A késői egyenirányító kálium áram mindkét (gyors és lassú) komponensének amplitúdója megnőtt, de csak a kalcium koncentráció élettani értékei mellett. - Megvizsgáltuk az elektrofiziológiában széleskörűen használt két drog, a nátrium csatorna gátló tetrodotoxin és a CaMKII gátló KN-93 hatásának szelektivitását. Méréseink szerint a tetrodotoxin közepes affinitást mutat az L-típusú kalcium csatornához, míg a KN-93 már a CaMKII IC50 értékénél kisebb koncentrációban gátolja a késői egyenirányító kálium áram gyors komponensét. - Tanulmányoztuk és jellemeztük a ß-adrenerg/CaMKII stimuláció hatását az emlős szív legjelentősebb ionáramaira, illetve azok koordinációjára. - Vizsgáltuk a szív több ionáramának kalcium függését a sejtplazma kalcium koncentrációjának pufferelése segítségével. A projekt eredményeiből 20 tudományos közlemény született, melyeknek kummulatív impakt faktora 62.728.
Results in English
The central goal of the project was to determine how CaMKII modulates the function of cardiac ion channels, and how these modulations influence the frequency response and beat to beat variation of the action potential. Within the framework of the project we the following results were produced: - In rabbit heart failure model elevated CaMKII activity increases late sodium current and sodium-calcium exchanger. Both rapid and slow delayed rectifier potassium currents were significantly upregulated in heart failure during the action potential, but only when measured in the presence of physiologic calcium cycling. - We investigated the selectivity of tetrodotoxin and KN-93 used in electrophysiology as specific inhibitor for sodium channel and CaMKII respectively. Our data indicate that tetrodotoxin possesses moderate affinity to L-type calcium channels. KN-93 inhibits early component of delayed rectifier potassium current at lower concentration than that of IC50 of CaMKII. - Impact of ß-adrenergic/CaMKII stimulation was characterized on the kinetics and coordination of major ionic currents in mammalian myocardium. - We studied the calcium dependent regulation of multiple cardiac ionic currents by buffering cytosolic calcium concentration. Number of research papers published in peer reviewed journals: 20 with cumulative impact factor of 62.728.
Full text https://www.otka-palyazat.hu/download.php?type=zarobeszamolo&projektid=101196
Decision
Yes





 

List of publications

  
Horvath B, Banyasz T, Jian Z, Hegyi B, Kistamas K, Nanasi PP, Izu LT, Ye CI: Dynamics of the late Na+ current during cardiac action potential and its contribution to afterdepolarizations., Journal of Molecular and Cellular Cardiology, 2013; 64: 59-68., 2013
Hegyi B, Barandi L, Komaromi I, Papp F, Horvath B, Magyar J, Banyasz T, Krasznai Z, Szentandrassy N, Nanasi PP.: Tetrodotoxin blocks L-type Ca2+ channels in canine ventricular cardiomyocytes, Pflugers Archiv-European Journal of Physiology, 2012; 464: 167-174., 2012
Szabo L, Szentandrassy N, Kistamas K, Hegyi B, Ruzsnavszky F, Vaczi K, Horvath B, Magyar J, Banyasz T, Pal B, Nanasi PP.: Effects of tacrolimus on action potential configuration and transmembrane ion currents in canine ventricular cells., Naunyn-Schmiedebergs Archives of Pharmacology, 2013; 386: 239-246., 2013
Kistamas K, Szentandrassy N, Hegyi B, Ruzsnayszky F, Vaczi K, Barandi L, Horvath B, Szebeni A, Magyar J, Banyasz T, Kecskemeti V, Nanasi PP.: Effects of pioglitazone on cardiac ion currents and action potential morphology in canine ventricular myocytes, European Journal of Pharmacology, 2013; 710: 10-19., 2013
Hegyi B, Komaromi I, Kistamas K, Ruzsnavszky F, Vaczi K, Horvath B, Magyar J, Banyasz T, Nanasi PP, Szentandrassy N.: Tetrodotoxin Blockade on Canine Cardiac L-Type Ca2+ Channels Depends on pH and Redox Potential., Marine Drugs, 2013; 11: 2140-2153., 2013
Ruzsnavszky F, Hegyi B, Kistamás K, Váczi K, Horváth B, Szentandrássy N, Bányász T, Nánási PP, Magyar J: Asynchronous activation of calcium and potassium currents by isoproterenol in canine ventricular myocytes, Naunyn Schmiedeberg's Arch Pharmacol 2014;387:457-467, 2014
Banyasz T, Jian Z, Horvath B, Khabbaz S, Izu LT, Chen-Izu Y: Beta-adrenergic stimulation reverses the I-Kr-I-Ks dominant pattern during cardiac action potential., Pflugers Archiv - European Journal of Physiology 2014; 466(11): 2067-2076., 2014
Szentmiklósi AJ, Szentandrássy N, Hegyi B, Horváth B, Magyar J, Bányász T, Nánási PP: Chemistry, physiology, and pharmacology of β-adrenergic mechanisms in the heart. Why are β-blocker antiarrhythmics superior?, Curr Pharm Design 2015;21:1030-1041, 2015
Váczi K, Hegyi B, Ruzsnavszky F, Kistamás K, Horváth B, Bányász T, Nánási PP, Szentandrássy N, Magyar J: : 9-anthracene carboxylic acid is more suitable than DIDS for characterization of calcium-activated chloride current during canine ventricular action potential, Naunyn Schmiedeberg's Arch Pharmacol 2015; 388:87-100, 2015
Szentandrassy N, Nagy D, Hegyi B, Magyar J, Bányász T, Nánási PP: Class IV antiarrhythmic agents: new compounds using an old strategy., Curr Pharm Design 2015;21:977-1010, 2015
Magyar J, Bányász T, Szentandrássy N, Kistamás K, Nánási PP, Satin J: Role of gap junction channel in the development of beat-to-beat action potential repolarization variability and arrhythmias, Curr Pharm Design 2015;21:1042-1052, 2015
Banyasz T, Szentandrássy N, Magyar J, Szabó Z, Nánási PP, Chen-Izu Y, Izu LT: An emerging antiarrhythmic target: late sodium current, Curr Pharm Design 2015;21:1073-1090, 2015
Kistamás K, Szentandrássy N, Hegyi B, Váczi K, Ruzsnavszky F, Horváth B, Bányász T, Nánási PP, Magyar J: Changes in intracellular calcium concentration influence beat-to-beat variability of action potential duration in canine ventricular myocytes, J Physiol Pharmacol 2015;66:73-81, 2015
Kistamás K, Hegyi B, Váczi K, Horváth B, Bányász T, Magyar J, Szentandrássy N, Nánási PP: Oxidative shift in tissue redox potential increases beat-to-beat variability of action potential duration., Canadian J Physiol Pharmacol 2015;93:527-, 2015
Horváth B, Hegyi B, Kistamás K, Váczi K, Bányász T, Magyar J, Szentandrássy N, Nánási PP: Cytosolic calcium changes affect the incidence of early afterdepolarizations in canine ventricular myocytes, Canadian J Physiol Pharmacol 2015;93:563-568, 2015
Magyar J, Kistamás K, Váczi K, Hegyi B, Horváth B, Bányász T, Nánási PP, Szentandrássy N: Concept of relative variability of cardiac action potential duration and its test under various experimental conditions, Gen Physiol Biophys 2016;35:55-62, 2015
Hegyi B, Chen-Izu Y, Jian Z, Shimkunas R, Izu LT, Banyasz T: KN-93 inhibits IKr in mammalian cardiomyocytes, Journal of Molecular and Cellular Cardiology 89 (2015) 173–176, 2015
Szentandrassy, N. Kistamas, K. Hegyi, B. Horvath, B. Ruzsnavszky, F. Vaczi, K. Magyar, J. Banyasz, T. Varro, A. Nanasi, P. P.: Contribution of ion currents to beat-to-beat variability of action potential duration in canine ventricular myocytes, Pflügers Archive 467(7):1431-1443, 2015
Szentmiklósi AJ, Szentandrássy N, Hegyi B, Horváth B, Magyar J, Bányász T, Nánási PP: Chemistry, physiology, and pharmacology of β-adrenergic mechanisms in the heart. Why are β-blocker antiarrhythmics superior?, Curr Pharm Design 2015;21:1030-1041, 2015
Magyar J, Bányász T, Szentandrássy N, Kistamás K, Nánási PP, Satin J: Role of gap junction channel in the development of beat-to-beat action potential repolarization variability and arrhythmias, Curr Pharm Design 2015;21:1042-1052, 2015
Hegyi B, Banyasz T, Shannon TR, Chen-Izu Y, Izu LT: Electrophysiological Determination of Submembrane Na+ Concentration in Cardiac Myocytes, Biophysical Journal 111(6):1304-1315, 2016
Horvath B, Vaczi K, Hegyi B, Gonczi M, Dienes B, Kistamas K, Banyasz T, Magyar J, Baczko I, Varro A, Seprenyi G, Csernoch L, Nanasi PP, Szentandrassy N: Sarcolemmal Ca2+-entry through L-type Ca2+ channels controls the profile of Ca2+-activated Cl- current in canine ventricular myocytes, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY 97:125-139, 2016
Magyar J, Kistamas K, Vaczi K, Hegyi B, Horvath B, Banyasz T, Nanasi PP, Szentandrassy N: Concept of relative variability of cardiac action potential duration and its test under various experimental conditions, GENERAL PHYSIOLOGY AND BIOPHYSICS 35(1):55-62, 2016




 

Events of the project

  
2016-05-04 13:28:26
Résztvevők változása



Back »