The intricacies of atrial calcium cycling during excitation-contraction coupling

Introduction In the heart, excitation-contraction coupling (ECC) is a sequence of events that begins with membrane depolarization by an action potential (AP), followed by activation of voltage-gated Ca channels in the surface membrane, initiation of Ca release from the SR Ca store by CICR, and the resulting contraction. Most of our knowledge of the mechanistic details of ECC originates from studies of ventricular muscle. However, seminal studies on atrial ECC and Ca signaling, while documenting important similarities between atrial and ventricular tissues, have revealed critical differences. A striking difference between atrial and ventricular myocytes is the presence of an extensive system of transverse tubules (t-tubules), which are surface membrane invaginations that extend throughout the entire ventricular myocyte and are organized in a sarcomeric pattern. The t-tubule system is an integral part of the surface membrane that allows the placement of voltage-gated L-type Ca channels (LCCs) in close vicinity to clusters of RyR Ca release channels in the SR membrane. Each of these Ca release units (CRUs) therefore has its own source of activator Ca in form of a small number of adjacent LCCs. As a consequence of these structural arrangements, Ca release during ventricular ECC is spatially homogeneous throughout the cell. In contrast, atrial myocytes either lack t-tubules or have only a sparse and irregular system (Hüser et al., 1996; Mackenzie et al., 2001; Bootman et al., 2006; Smyrnias et al., 2010), creating important ramifications for atrial Ca dynamics during ECC. In the following, we focus on atrium-specific features of the initiation of ECC and SR Ca release before turning to a discussion of SR Ca depletion and release termination.