Thesis topic proposal
Norbert Nagy
Investigation of the cardiac Na+/Ca2+ exchanger: from physiology to arrhythmias


Institute: University of Szeged
theoretical medicine
Doctoral School of Multidisciplinary Medical Scienses

Thesis supervisor: Norbert Nagy
Location of studies (in Hungarian): Department of Pharmacology and Pharmacotherapy, 6720 Szeged, Dóm tér 12.
Abbreviation of location of studies: ÁOK

Description of the research topic:

The cardiac action potential and Ca2+ cycle are tightly coupled processes. The Ca2+ ions enter to the cell during the plateau phase of the action potential, and after binding to the ryanodine receptor, releases considerable amount of stored intracellular Ca2+ from the sarcoplasmic reticulum (SR). The released Ca2+ (Ca2+ transient) can be easily monitored with fluorescent dyes. The interaction of intracellular Ca2+ with the myofilaments achieves the cardiac contraction, then the SR Ca2+ ATPase reuptakes the majority of the released Ca2+ to establish the relaxation. In the same time, a smaller amount of Ca2+ are extruded from the cell via the Na+/Ca2+ exchanger (NCX). The function of the NCX strictly depends on the intra- and extracellular Na+ and Ca2+ levels and the actual membrane potential. The main operational mode of the NCX during an action potential is Ca2+ extrusion (forward mode) when the intracellular Ca2+ is removed from the cell, but for a short time, the NCX can gain the intracellular Ca2+ level via reverse mode activity, in the beginning of the action potential.
Certain cardiac diseases shift the actual level of the intracellular Na+ and Ca2+ ions, and in the same time the duration of the action potential also could be changed. Since these factors are crucial determinants in the actual function of the exchanger, the mechanism of several arrhythmias may be tightly coupled with altered NCX function. Our current knowledge about the NCX is insufficient by the lack of selective NCX inhibitor. Since our laboratory currently the only one which has a properly effective and selective NCX inhibitor, we have an opportunity to better understand the cardiac NCX function including its physiology, pathophysiology and pharmacology. In this topic we focus on the following questions: How does the NCX contribute in the shaping of the cardiac action potential and what is the consequence of its inhibition on the action potential characteristic? Has any role of NCX in the spontaneous automacy in the sinus node cells? Has the NCX inhibition positive inotropic effect? What is the role of the NCX-mediated arrhythmias and has the NCX inhibition antiarrhythmic activity?

Required language skills: English
Further requirements: 
TDK munka

Number of students who can be accepted: 1

Deadline for application: 2019-12-19

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