L-Type Ca2+ Current in Cardiac Arrhythmias

Abstract

Cardiac arrhythmias result from the confluence of structural and functional changes in the heart and genetic predisposition, reflecting an interaction between a susceptible substrate (e.g. an anatomically defined circuit, a myocardial scar, fibrosis or a monogenic arrhythmia syndrome) and a specific electrophysiological triggering event. Such triggered activities arises from delayed afterdepolarizations (DADs) or early afterdepolarizations (EADs), in which action potential prolongation and aberrant Ca2+ fluxes are a recurrent theme. Ca2+ channels in cardiomyocytes provide the main influx pathway for Ca2+. Three types of high threshold Ca2+ channels are expressed in heart: two L-type channels, Cav1.2 and Cav1.3 and a P-type channel, Cav2.1. The Cav2.1 channel protein is expressed at a very low level the in heart (Starr et al., 1991) while Cav1.3 is mainly expressed in fetal hearts and only in adult sinoatrial and atrioventricular nodes and atrial tissues of adult (Lipscombe et al., 2004; Qu et al., 2005). We will focus attention on the Cav1.2 L-type Ca2+ channel (LTCC) which is the main player in electrical activity and excitation-contraction coupling (EC coupling) in the ventricular cardiomyocyte. The LTCC of cardiomyocytes is a complex multimeric molecular sarcolemmal ensemble that during an action potential (AP) allows Ca2+ to flow down its electrochemical gradient into the cardiac cell. LTCCs are mostly localized in the transverse tubular system of cardiomyocytes (Wibo et al., 1991; Kawai et al., 1999; Brette et al., 2004). Activation of LTCC generates a Ca2+ current (ICaL) through the sarcolemma large enough to be involved in AP overshoot and in the control of AP duration (APD) in different cardiac cells types (Bers, 2001). ICaL serves as a trigger for Ca2+ release from the sarcoplasmic reticulum (SR) during the excitation-contraction coupling by a mechanism known as calcium-induced calcium release (CICR, Fabiato & Fabiato, 1975; Bers, 2001). LTCC activation can also play a role in transcription mechanisms in cardiomyocytes (Atar et al., 1995; Brette et al., 2006). Several hormones and neuromediators modulate the activity of LTCC via complex intracellular signaling pathways and, as well, several intracellular molecules and the cytoskeleton can influence LTCC activity (Benitah et al., 2010). However, intracellular Ca2+ concentration is strictly controlled in normal cells by different mechanisms (Bers, 2001) since a Ca2+ overload can have deleterious effects including arrhythmias and myocardial remodeling via a genetic reprogramming of the cardiac cell (Benitah et al., 2003).