Chloride channels and transporters – role in the electrical activity of pacemaker and working myocardium

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Abstract

Chlorine anions have a significant influence on the electrophysiological properties of excitable tissues, including myocardium. Chlorine anions and transmembrane chloride currents (ICl) determine the configuration of action potentials (AP) in various regions of hearts. Disruption of transmembrane chloride transport leads to alterations in normal electrical activity, resulting in cardiac pathologies and arrhythmias. Currently, chloride conductivity and expression in the heart and a functional role have been confirmed for several types of macromolecules. These channels include CFTR, ClC-2, CaCC (TMEM16), and VRAC (LRRC8x). Additionally, chloride cotransporters (KCC, NKCC) and chloride-bicarbonate exchangers make a significant contribution to the regulation of intracellular chlorid ion concentration ([Cl-]i) and, consequently, the equilibrium potential for chloride ions (ECl). The review covers the mechanisms by which chloride transmembrane transport influences the bioelectrical activity of cardiomyocytes and the potential functions of chloride and chloride currents in specialized regions of the heart.

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About the authors

Y. A. Voronina

Moscow State University; Chazov National Medical Research Centre of Cardiology

Author for correspondence.
Email: voronina.yana.2014@post.bio.msu.ru

Department of Human and Animal Physiology, Faculty of Biology; Smirnov Institute of Experimental Cardiology

Russian Federation, Moscow, 119234; Moscow, 121552

A. M. Karhov

Moscow State University; Chazov National Medical Research Centre of Cardiology

Email: akarchoff@gmail.com

Department of Human and Animal Physiology, Faculty of Biology; Smirnov Institute of Experimental Cardiology

Russian Federation, Moscow, 119234; Moscow, 121552

V. S. Kuzmin

Moscow State University; Chazov National Medical Research Centre of Cardiology

Email: ku290381@mail.ru

Department of Human and Animal Physiology, Faculty of Biology; Smirnov Institute of Experimental Cardiology

Russian Federation, Moscow, 119234; Moscow, 121552

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2. Fig. 1. The range of values ​​of the equilibrium potential for chlorine (ECl–) in cardiomyocytes. The extracellular concentration of chlorine ([Cl–]o) is 125 mM. a – dependence of ECl– on [Cl–]i. The yellow part of the dotted curve denotes the physiological range of possible [Cl–]i and ECl in cardiomyocytes of different parts of the heart, the red and green parts of the dotted curve – possible values ​​of [Cl–]i and ECl in cardiomyocytes under hypotonic and hypertonic stress; b – action potential in cardiomyocytes of the contractile (working) myocardium. The area marked in red is the range of ECl– changes depending on [Cl–]i; c – action potential in cardiomyocytes of the sinoatrial node with pacemaker activity. The black and gray triangles are the MP values, up to which the incoming depolarizing component of ICl takes place (at a given value of [Cl–]i). ICl, in, dep – depolarizing incoming chloride current, MP – membrane potential.

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3. Fig. 2. Upper panels: changes in the configuration of the action potential of cardiomyocytes of the working (left) and pacemaker (right) myocardium upon activation of chloride channels. Black: action potential in the control, red: action potential upon activation of different types of chloride channels: CFTR (a–b), LRRC8x (a–b), ClC-2 (c–d), TMEM16A (d–f). Lower panels: changes in the chloride current through different chloride channels depending on the membrane potential during the action potential of cardiomyocytes of the working (left) and pacemaker (right) myocardium: CFTR (a–b), LRRC8x (a–b), ClC-2 (c–d), TMEM16A (d–f). Green: inward current (chlorine ions leave the cell), blue: outward current (chlorine ions enter the cell). In panel b, the inward and outward components of the current are shown for three values ​​of [Cl–]i, since this value may differ between the central and peripheral parts of the heterogeneous SAN tissue, causing different electrophysiological effects. The curves are constructed using the Goldman–Hodgkin–Katz (GKH) equation for the transmembrane ion current and taking into account the probability of the channel being in the open state.

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4. Fig. 3. Properties of the calcium-dependent chloride current Ito,2 of the TMEM16A (Ano1) channel: a – current-voltage characteristic of Ito,2 at different stimulation frequencies (0.1–2.5 Hz). Given with modifications from Wang Zh. et al., Am. J. Physiol., 268, No. 1992–H2002, 1995; b – original recordings of Ito,2 with a stepwise protocol of changing the maintained potential from –20 to +60 mV. Given with modifications from Li G-R et al., Am. J. Physiol., 269, No. 463–H472, 1995; c – interaction of the calcium-dependent chloride channel TMEM16A (ANO1), which is a molecular substrate of Ito,2, with various proteins. ANO1 – calcium-dependent chloride channel TMEM16A, CLCA1, CLCA2, CLCA4 – regulatory subunits of chloride channels, BEST1, BEST2, BEST3 – bestrophins 1–3, CFTR – cystic fibrosis transmembrane regulator, SLC26A6 – chloride-bicarbonate exchanger, TTYH3 – tweety family protein; g – representative examples of spontaneous “calcium waves” recorded in isolated cardiomyocytes. Top – Fluo-4 fluorescence curves obtained by averaging the values ​​along a 5 μm scan line, bottom – pseudo-images reflecting the change in fluorescence level over time (over 300 ms) along the scan line (horizontal axis – time, vertical axis – scan line).

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5. Fig. 4. Electrical characteristics of chlorine-cation cotransporters: a – dependence of electromotive force (EMF) on membrane potential (MP) for potassium, chlorine ions and cotransporter KCC; b – dependence of electromotive force (EMF) on membrane potential (MP) for sodium, potassium, chlorine ions and cotransporter NKCC; c – current-voltage characteristic of potassium and chlorine currents, as well as total current of cotransporter KCC; d – current-voltage characteristic of sodium, potassium and chlorine currents, as well as total current of cotransporter NKCC.

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6. Fig. 5. Effects of activation of chloride-cation cotransporters on the electrical activity of the working myocardium: a – change in the configuration of the action potential of the cardiomyocyte of the working myocardium upon activation of the cotransporter of chloride and potassium ions KCC (red, taking into account the activity of KCC) compared to the control (black, excluding the activity of KCC); b – change in the configuration of the action potential of the cardiomyocyte of the working myocardium upon activation of the cotransporter of chloride and potassium ions NKCC (red, taking into account the activity of NKCC) compared to the control (black, excluding the activity of NKCC); c – change in the intensity of the flow of chloride ions through the cotransporters KCC and NKCC depending on the membrane potential.

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