Functional role of voltage gated Ca(2+) channels in heart automaticity

Abstract

Pacemaker activity of automatic cardiac myocytes controls the heartbeat in everyday life. Cardiac automaticity is under the control of several neurotransmitters and hormones and is constantly regulated by the autonomic nervous system to match the physiological needs of the organism. Several classes of ion channels and proteins involved in intracellular Ca(2+) dynamics contribute to pacemaker activity. The functional role of voltage-gated calcium channels (VGCCs) in heart automaticity and impulse conduction has been matter of debate for 30 years. However, growing evidence shows that VGCCs are important regulators of the pacemaker mechanisms and play also a major role in atrio-ventricular impulse conduction. Incidentally, studies performed in genetically modified mice lacking L-type Cav1.3 (Cav1.3(-/-)) or T-type Cav3.1 (Cav3.1(-/-)) channels show that genetic inactivation of these channels strongly impacts pacemaking. In cardiac pacemaker cells, VGCCs activate at negative voltages at the beginning of the diastolic depolarization and importantly contribute to this phase by supplying inward current. Loss-of-function of these channels also impairs atrio-ventricular conduction. Furthermore, inactivation of Cav1.3 channels promotes also atrial fibrillation and flutter in knockout mice suggesting that these channels can play a role in stabilizing atrial rhythm. Genomic analysis demonstrated that Cav1.3 and Cav3.1 channels are widely expressed in pacemaker tissue of mice, rabbits and humans. Importantly, human diseases of pacemaker activity such as congenital bradycardia and heart block have been attributed to loss-of-function of Cav1.3 and Cav3.1 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 Ca(2+) entry through VGCCs could influence intracellular Ca(2+) handling and promote atrial arrhythmias.

Keywords: L-type Ca2+ channel; T-type Ca2+ channels; atrioventricular node; heart automaticity; sinoatrial node.

Figure 1

Importance of L-type VGCCs in cardiac automaticity. (A) Representative recordings of consecutive action potentials recorded in pacemaker cells from wild-type (top left panel) and Ca_v1.3^−/− mice (top right panel). Cellular arrhythmia is evident as irregular cycle length duration in Ca_v1.3^−/− cells (bottom right panel) compared with wild-type cells (bottom left panel). Dotted lines indicate the zero voltage level (Data from Mangoni et al., 2003). (B) Telemetric ECGs showing prolongation of RR interval PQ interval in Ca_v1.3^−/− mice (top right panel) with respect to wild type littermates (top left panel). (C) Dot plot of beat to beat variability in wild-type (left panel) and Ca_v1.3^−/− mice (right panel) observed during 10 min recordings. Note the dispersion of the RR intervals in Ca_v1.3 knockout mice, revealing strong sinus arrhythmia. The dotted lines indicate the average heart rate as the number of beats per minutes (bpm) (reprinted from Mangoni et al., , with permission from Elsevier).

Figure 2

Properties of VGCCs in cardiac pacemaker cells. (A) I–V curve (top left panel) and steady-state inactivation (top right panel) of native SAN Ca_v3.1 (dashed curve), Ca_v1.3 (solid curve), and Ca_v1.2 (dotted curve) channels (reprinted from Mangoni et al., , with permission from Elsevier). Examples of voltage dependent calcium currents recorded in pacemakers cells from WT (middle and bottom left panel), Ca_v1.3^−/− (middle right panel) and Ca_v3.1^−/− mice (bottom right panel). (B) Top left panel: I–V curve of L-type Ca²⁺ channels obtained from WT (black open circles) and Ca_v1.3^−/− (gray open circles) isolated AVN cells. Top right panels: current to voltage relationship in isolated AVN cells from WT and Ca_v3.1^−/− mice. Sample traces of I_Ca,L (middle panels) and I_Ca,T (bottom panels) recorded in isolated AVN cells from WT, Ca_v1.3^−/− and Ca_v3.1^−/− mice. For I_Ca,L recordings the holding potential (V_h) was set at −55 mV, for Ca_v3.1 at −90 mV. Test potential (V_t) is reported near the trace (reprinted from Mangoni et al., with permission from Wolters Kluwer Health).

Figure 3

Role of T-type VGCCs in cardiac automaticity. (A) Representative sweeps of spontaneous action potentials obtained from SAN cells from WT (upper left trace) and Ca_v3.1^−/− mice (lower left trace). Right panel: Superimposition of typical action potentials from a WT and from Ca_v3.1^−/− SAN cell. (B) Histograms of the average bpm value and the slope of the diastolic depolarization (SDD). (C) Representative telemetric ECG recordings obtained on WT (left panel) and Ca_v3.1^−/− animals (right panel). (D) Variation of heart rate (in bpm) in WT (left panel) and Ca_v3.1^−/− mice (right panel) over a 24-h period. Dashed lines indicate mean day and night heart rates (reprinted from Mangoni et al., with permission from Wolters Kluwer Health).

Figure 4

Cardiac VGCCs in cardiac automaticity pathology. (A) ECG sample recordings from WT (a) and Ca_v1.3^−/− mice (b). (B) ECG recordings from a healthy person (a) and three individuals with SANDD syndrome (b–d). Asterisks mark P waves that precede QRS complexes; arrows indicate waveforms that suggest P waves coinciding with T waves; hashes indicate not conducted P waves. Numbers indicate heart rate (bpm) calculated from the corresponding beat-to-beat R-R interval (adapted from Baig et al., 2011). (B) Telemetric surface ECGs of freely moving WT, Ca_v3.1^−/−, Ca_v1.3^−/−, and Ca_v1.3^−/−/Ca_v3.1^−/− mice showed additive effect of Ca_v gene inactivation on atrioventricular conduction dysfunction. Solid bars indicate PQ interval, dotted bars indicate RR intervals and arrows indicate isolated P waves (reprinted from Marger et al., with permission from Taylor and Francis LLC http://www.tandfonline.com).