Can the sodium-calcium exchanger initiate or suppress calcium sparks in cardiac myocytes?

Positive feedback of Calcium (Ca)-induced Ca release is the mechanism of Ca spark formation in cardiac myocytes. To initiate this process, a certain amount of Ca in the cleft space is necessary. When the membrane potential becomes higher during excitation-contraction coupling, Ca can enter through both Ca current (I(CaL)) and sodium-calcium exchanger (NCX) and may activate ryanodine receptors to initiate a Ca spark. On the other hand, at the resting membrane potential (V(m) ~-80 mV), NCX removes Ca from the cell (forward mode). If Ca released from the sarcoplasmic reticulum is quickly removed via forward mode NCX before Ca-induced Ca release starts, the Ca release becomes nonspark Ca leak. This would also be influenced by the cleft/noncleft distribution of NCX, which is unknown. Using a physiologically detailed mathematical model of subcellular Ca cycling, we analyze how NCX strength and distribution alter Ca spark formation. During excitation-contraction coupling, most Ca sparks are induced by I(CaL) with very few due to NCX current. At the resting membrane potential if most NCX is localized to the cleft, spontaneous Ca sparks are significantly reduced.