Mechanistic and molecular factors determining RyR2 refractoriness and its role in healthy cardiac function and arrhythmogenesis. RyR2 refractoriness is primarily determined by effects on RyR2 of luminal Ca, i.e., luminal deactivation, and modulated by other factors, including Ca-dependent inhibition of RyR2 by CaM, RyR2 phosphorylation and oxidation, and changes in SR Ca uptake. RyR2 refractoriness is essential for healthy cardiac relaxation and rhythm. Genetic and acquired defects in RyR2 complex result in shortened RyR2 refractoriness, synchronized aberrant Ca cycling, and arrhythmia.