Quenching the spark: Termination of CICR in the submicroscopic space of the dyad

Introduction Cardiac excitation–contraction coupling is a transduction cascade that results in muscle contraction and relaxation. In ventricular myocytes, the arrival of an action potential activates sarcolemmal L-type Ca channels, and the subsequent inward Ca current, in turn, activates several RyRs in the SR membrane (the Ca release unit [CRU]). Activation of a CRU causes more Ca to be released into the local cytoplasm in a process called CICR (Fabiato, 1983) and is observed as a Ca spark (Cannell et al., 1994). The spatiotemporal summation of these elementary events forms a cell-wide Ca transient that enables cross-bridge cycling. The rise in cytosolic Ca is short-lived, as removal mechanisms such as the Na–Ca exchange and SR Ca ATPase (SER CA) restore Ca back to resting conditions, once SR Ca release stops by one or more mechanisms whose relative contributions remain unclear (Hinch, 2004; Stern and Cheng, 2004), but, as we discuss below, one mechanism—induction decay—can by itself explain the termination of CICR.