Phosphorylation of the cardiac ryanodine receptor (RyR2) is a key mechanism 
regulating sarcoplasmic reticulum (SR) Ca2+ release. Differences in opinion have 
arisen over the importance assigned to specific phosphorylation sites on RyR2, 
over the kinase (s) suggested to directly phosphorylate RyR2 and surrounding the 
possibility that altered phosphorylation of RyR2 is associated with contractile 
dysfunction observed in heart failure. Ca2+/calmodulin dependent protein kinase 
II (CaMKII) can phosphorylate RyR2 and modulate its activity. This 
phosphorylation positively modulates cardiac inotropic function but in extreme 
situations such as heart failure, elevated CaMKII activity can adversely 
increase Ca2+ release from the SR and lead to arrhythmogenesis. Although other 
kinases can phosphorylate RyR2, most notably cAMP-dependent protein kinase 
(PKA), evidence for a key role of CaMKII in mediating RyR2-dependent Ca2+ 
release is emerging. Future challenges include (i) fully identifying mechanisms 
of CaMKII interaction with the RyR2 complex and (ii) given the ubiquitous 
expression of CaMKII, developing selective strategies to modulate RyR2-targeted 
CaMKII activity and allow improved understanding of its role in normal and 
diseased heart.