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Functional Role of Voltage Gated Ca Channels in Heart Automaticity

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Functional Role of Voltage Gated Ca Channels in Heart Automaticity REVIEW ARTICLE published: 02 February 2015 doi: 10.3389/fphys.2015.00019 Functional role of voltage gated Ca2+ channels in heart automaticity Pietro Mesirca 1,2,3*, Angelo G. Torrente 1,2,3 and Matteo E. Mangoni 1,2,3 1 Laboratory of Excellence in Ion Channel Science and Therapeutics, Département de Physiologie, Institut de Génomique Fonctionnelle, Montpellier, France 2 UMR-5203, Centre National de la Recherche Scientifique, Universités de Montpellier 1 and 2, Montpellier, France 3 INSERM U 1191, Département de Physiologie, Universités de Montpellier 1 and 2, Montpellier, France Edited by: Pacemaker activity of automatic cardiac myocytes controls the heartbeat in everyday life. Ming Lei, University of Oxford, UK Cardiac automaticity is under the control of several neurotransmitters and hormones and Reviewed by: is constantly regulated by the autonomic nervous system to match the physiological needs Arie O. Verkerk, University of of the organism. Several classes of ion channels and proteins involved in intracellular Ca2+ Amsterdam, Netherlands Yue-kun Ju, University of Sydney, dynamics contribute to pacemaker activity. The functional role of voltage-gated calcium Australia channels (VGCCs) in heart automaticity and impulse conduction has been matter of debate *Correspondence: for 30 years. However, growing evidence shows that VGCCs are important regulators Pietro Mesirca, Laboratory of of the pacemaker mechanisms and play also a major role in atrio-ventricular impulse Excellence in Ion Channel Science conduction. Incidentally, studies performed in genetically modified mice lacking L-type and Therapeutics, Département de −/− −/− Physiologie, Institut de Génomique Cav1. 3 ( C a v1. 3 )orT-typeCav3.1 (Cav3.1 ) channels show that genetic inactivation of Fonctionnelle; these channels strongly impacts pacemaking. In cardiac pacemaker cells, VGCCs activate UMR-5203, Centre National de la at negative voltages at the beginning of the diastolic depolarization and importantly Recherche Scientifique, Universités contribute to this phase by supplying inward current. Loss-of-function of these channels de Montpellier 1 and 2; INSERM U 1191, Département de also impairs atrio-ventricular conduction. Furthermore, inactivation of Cav1.3 channels Physiologie, Universités de promotes also atrial fibrillation and flutter in knockout mice suggesting that these channels Montpellier 1 and 2, 141 Rue de la can play a role in stabilizing atrial rhythm. Genomic analysis demonstrated that Cav1. 3 a n d Cardonille, 34094 Montpellier, Ca 3.1 channels are widely expressed in pacemaker tissue of mice, rabbits and humans. France v e-mail: [email protected] Importantly, human diseases of pacemaker activity such as congenital bradycardia and heart block have been attributed to loss-of-function of Cav1. 3 a n d C a v3.1 channels. In this article, we will review the current knowledge on the role of VGCCs in the generation and regulation of heart rate and rhythm. We will discuss also how loss of Ca2+ entry through VGCCs could influence intracellular Ca2+ handling and promote atrial arrhythmias. Keywords: heart automaticity, L-type Ca2+ channel, T-type Ca2+ channels, sinoatrial node, atrioventricular node INTRODUCTION The generation of the automaticity in cardiac pacemaker cells Pacemaker activity in the heart is generated by specialized is due to the diastolic depolarization, a spontaneous slowly depo- myocytes, able to generate periodical oscillations of their mem- larizing phase of the action potential cycle. During this phase brane potential. These cells are thus called “pacemaker” cells the membrane potential progressively becomes less negative until (Mangoni and Nargeot, 2008). Pacemaker cells are localized in it reaches the threshold for triggering a new action potential. the sino-atrial node (SAN), which is a thin tissue located in The SAN action potential cycle length determines the heart rate. the right atrium (for anatomical description see Dobrzynski At the level of the individual SAN cell, different classes of ion et al., 2005). Under physiological conditions the cardiac impulse channels of the plasma membrane, the sarcoplasmic reticulum hasoriginintheSAN.Thepacemakerimpulsespreadsfrom (SR) and mytochondria contribute to the generation and regu- the SAN to the cardiac conduction system (composed by the lation of automaticity, but their respective functional roles and atrioventricular node and Purkinje fibers network), driving the interactions are still not fully understood. contraction of the whole working myocardium. In comparison In the recent past, two distinct, but not mutually exclusively, to the rest of the conduction system, the SAN generates the hypotheses were proposed to explain the mechanism under- fastest intrinsic automaticity, thereby inhibiting pacemaking in ling the cardiac automaticity: the so-called “membrane clock” the atrioventricular node (AVN) and the Purkinje fibers network. model of pacemaking, which considers the “funny” current (If ), Nevertheless, in case of SAN failure, the AVN can take over as an inward Na+/K+ current activated by membrane hyperpolar- dominant pacemaker center. Under conditions of atrioventric- ization at negative voltages (Brown et al., 1979) and regulated ular block, Purkinje fibers are able to generate viable rhythm, directly by cAMP (Difrancesco and Tortora, 1991)asthekeyini- even if at relatively low rates (James, 2003; Dobrzynski et al., tiator of the diastolic depolarization (Difrancesco, 1991). In the 2013). “calcium clock” model of pacemaking the key mechanism in the www.frontiersin.org February 2015 | Volume 6 | Article 19 | 1 Mesirca et al. Calcium channels in heart automaticity diastolic depolarization is a spontaneous rhythmic phenomenon inward current during the diastolic depolarization phase (Zhang of Ca2+ release from the SR activating the Na+/Ca2+ exchanger et al., 2002, 2011; Mangoni et al., 2003, 2006b; Marger et al., (NCX) in forward mode. This NCX mediated inward current is 2011a) or by stimulating the NCX activated by subsarcolem- able to depolarize the membrane voltage to the threshold of the mal Ca2+ release during the diastolic depolarization (Lakatta following action potential (Bogdanov et al., 2001; Vinogradova et al., 2010). VGCCs also participate to the upstroke phase of et al., 2002). Recently, the Ca2+ clock view of pacemaking has theactionpotential(Hagiwara et al., 1988; Doerr et al., 1989; been updated into the “coupled-clock” model (Lakatta et al., Marger et al., 2011a). Here we will focus on two distinct fami- 2010). In the coupled-clock model of pacemaking, the activity of lies of VGCCs, the L-type and the T-type Ca2+ channels. L-type membrane ion channels and spontaneous Ca2+ release mutually VGCCs are expressed throughout the myocardium and are sen- entrain to generate pacemaking (Lakatta et al., 2010; Monfredi sitive to antagonist and agonist dihydropyridines (DHPs) such as et al., 2013). For a more extended description of the issues raised nifedipine and BAY K 8644 and are stimulated by PKA-dependent 2+ by the If - based and the Ca or coupled-clock models of pace- phosporylation (Striessnig, 1999; van der Heyden et al., 2005). making, the reader is referred to recent review by the principal In comparison with T-type channels, L-type VGCCs activate authors (Difrancesco, 2010; Lakatta et al., 2010; Monfredi et al., upon membrane depolarization at more positive potential, have 2013). Ca2+ and voltage dependent inactivation, as well as a higher However, either the If -based or the coupled clock models of single channel conductance (Perez-Reyes, 2003). T-type VGCCs pacemaking do not fully appreciate the role of VGCCs in pace- are activated at more negative potentials than L-type VGCCs. making. Indeed, in the If -based model of pacemaking the L-type The kinetic hallmark of native and heterogously expressed T- 2+ 2+ Ca current (ICa,L) is considered only as a determinant of the type mediated Ca current is slow criss-crossing activation and action potential upstroke and duration (Difrancesco, 1993, 2010). fast voltage dependent inactivation (Carbone and Lux, 1987). In the coupled-clock model of pacemaking, ICa,L is considered as Table 1 summarizes the main characteristics of the L- and T-type a major mechanism to replenish SR Ca2+ content at each pace- VGCCs isoforms involved in cardiac automaticity. The eluci- maker cycle (Vinogradova et al., 2002). Finally, both the If -based dation of the functional role of the cardiac VGCCs can give and the coupled-clock models grant only a limited role to T-type important insights into the mechanisms underlying different VGCCs (Vinogradova et al., 2002). SAN and conduction system pathologies. Indeed, failure of gener- However, during the last 10 years evidence accumulated show- ating the cardiac impulse underlies SAN bradycardia and rhyth- ing that VGCCs contribute directly to pacemaking by carrying mic disease. Diseases of the sinus node account for more than Table 1 | Characteristics of the L- and T-type VGCCs isoforms involved in cardiac automaticity. L-type VGCC (Cav1) T-type VGCC (Cav3) Cav1.2 Cav1.3 Cav3.1 Cav3.2 Expression Embryonic stage Embryonic stage Start to increase in the perinatal High in Embryonic heart tissue time period and becomes predominant and then decrease and disappear in the adulthood in adult heart Cardiac SAN, AVN, atria, PF SAN, AVN, atria, PF SAN, AVN, atria, PF networks, SAN, AVN, atria, PF networks, tissues networks, Ventricles networks, poorly or not poorly or not expressed in poorly expressed in ventricular
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