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.
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