Figure 5.
Human mutations affecting Ca2+ cycling proteins. Intracellular Ca2+ handling is the central coordinator of cardiac contraction and relaxation. Ca2+ entering through L-type channels (LTCC) triggers Ca2+ release (CICR) from the SR via the RyR2, and sarcomere contraction is initiated. Relaxation occurs with SR Ca2+ reuptake through the SERCA2a. Calstabin2 coordinates excitation and contraction by modulating RyR2 release of Ca2+. PLN, an SR transmembrane inhibitor of SERCA2a modulates Ca2+ reuptake. Dynamic regulation of these molecules is effected by PKA-mediated phosphorylation. Ca2+ may further function as a universal signaling molecule, stimulating Ca2+-calmodulin and other molecular cascades. Human mutations (orange text) in molecules involved in calcium cycling cause cardiac remodeling and heart failure. NCX, sodium/calcium exchanger.