Quenching the spark: Termination of CICR in the sub-microscopic space of the dyad

Cardiac excitation-contraction (E-C) coupling is a transduction cascade that results in muscle contraction and subsequent relaxation. In ventricular myocytes, the arrival of an action potential activates sarcolemmal L-type Ca2+ channels (LCCs), and the subsequent inward Ca2+ current (ICa), in turn, activates several ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR) membrane (the Ca2+ release unit, CRU). Activation of a CRU causes more Ca2+ to be released into the local cytoplasm in a process called Ca2+-induced Ca2+ release (CICR) (Fabiato, 1983), which is observed as a Ca2+ spark (Cannell et al., 1994). The spatio-temporal summation of these elementary events forms a cell-wide transient increase in Ca2+ that enables cross-bridge cycling. This rise in cytosolic Ca2+ is short-lived, because removal mechanisms such as the Na+-Ca2+ exchange (NCX) and SR Ca2+ ATPase (SERCA) restore Ca2+ back to resting conditions once one (or more) mechanism(s) halt Ca2+ release from the SR (Stern and Cheng, 2004; Hinch, 2004). The relative contributions of these various mechanism(s) remain unclear but, as we discuss below, one mechanism – induction decay – can by itself explain the termination of CICR.