Heart failure is a complex disorder involving maladap-tive responses that result in defective regulation and function of multiple biological systems. Central to our understanding of heart failure and to the ability to design and test novel therapeutic approaches that will prolong survival and improve quality of life for the millions of individuals worldwide is the need to gain a better understanding of the molecular pathogenesis of the disorder. In the search for molecular physiological defects in failing hearts, it is logical to examine the mechanism of excitationcontraction (EC) coupling in which cardiomyocyte membrane depolarization, because of the cardiac action potential, is translated into mechanical contraction in the heart. This system requires the normal function of 3 key elements:(1) calcium (Ca2+) entry via the voltage-gated Ca2+ channel (VGCC) on the plasma membrane (transverse tubule);(2) Ca2+ release via the ryanodine receptor/Ca2+ release channel (RyR2); and (3) Ca2+ uptake via the Ca2+-ATPase on the sarcoplasmic reticulum (SR)(Figure 1). Data from our laboratory have shown that RyR2s in failing hearts are defective because of a chronic hyperadrenergic state of heart failure that results in hyperphosphorylation of the channel by cAMP-dependent protein kinase (PKA). 1 PKA hyperphosphorylation makes the RyR2 channels in failing hearts leaky by depleting these macromolecular complexes of the stabilizing protein FK506 binding protein (FKBP12. 6). One of the roles of FKBP12. 6 is to stabilize the RyR2 in the closed state during diastole to ensure against an aberrant SR Ca2+ leak, which can trigger cardiac arrhythmias by initiating delayed afterdepolarizations (DADs). 2, 3 We have shown that PKA phosphorylation of RyR2 at serine 2809 causes dissociation of FKBP12. 6 from the channels. 1 RyR2s are homotetramers comprised of 4 RyR2 monomers, each of which has a single PKA phosphorylation site (serine 2809) and binds one FKBP12. 6. Transient PKA phosphorylation of 1, 2, or 3 of the 4 PKA sites on RyR2 and the concomitant dissociation of 1, 2, or 3 of the 4 FKBP12. 6 bound to the channel transiently increases the activity of the channel by shifting the Ca2+ dependence for activation to the left. Dephosphorylation of