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.