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Figure 3 Regulatory systems of cardiac excitation-contraction coupling and the gene therapy targeting sarcoplasmic reticulum (SR) calcium uptake. (A) Intracellular mobilization of calcium ions governs myofilament contraction and relaxation. Two calcium release channels, the L-type calcium channel and ryanodine receptor (RyR), and a regulator of SR calcium uptake, phospholamban (PLN), are key controllers of calcium mobilization under the control of 2 second-messenger-regulated kinases, cyclic adenosine monophosphate (AMP)-dependent kinase (PKA) and calcium-calmodulin-dependent kinase II (CaMKII) (42). S16EPLN therapy directly targets SR calcium uptake (see text for details). (B) A working model of PLN-dependent SR calcium ATPase 2 (SERCA2) regulation has been refined, based on recent studies by Mueller et al. (61) and Zamoon et al. (62). Phospholamban is tightly bound to SERCA2 due to their low dissociation constant. Physiologically, high calcium concentration or PLN phosphorylation induces conformational changes of the cytoplasmic domain of PLN, which results in a structural rearrangement of PLN-SERCA2 interaction (from an inactive complex to an active complex) without dissociation. S16EPLN structurally resembles the Ser16-phosphoylated form PLN. Thus, S16EPLN transfection may stably constitute an active SERCA2-S16EPLN complex in cardiomyocytes. ARK = adrenergic receptor kinase; ßAR = beta-adrenergic receptor; FKBP = K506 binding protein; NCX = Na-Ca exchanger.