It is suggested that
protein kinase A (PKA)-dependent phosphorylation of cardiac
ryanodine receptors (
RyR2) is linked to the development of
heart failure and the generation of fatal
cardiac arrhythmias. It is also suggested that
RyR2 is phosphorylated to 75% of maximum levels in
heart failure resulting in leaky, unregulated channels gating in subconductance states. We now demonstrate that this is unlikely, as
RyR2 isolated from nonfailing cardiac muscle is phosphorylated to 75% of maximum at serine-2809, and in this situation,
RyR2 displays low open probability (P(o)) (0.059+/-0.010 [SEM];
n=30) and normal regulation of gating by Ca(2+) and other
ligands. However, when serine-2809 is PKA phosphorylated to maximum levels on
RyR2, unique changes in channel behavior are observed. The channel displays enhanced single-channel conductance, very long open states causing large increases in P(o), and no evidence of subconductance states. Dephosphorylation of channels by
protein phosphatase 1 (from 75% to near 0% at
serine-2809) also enhances
RyR2 channel activity through abbreviation of closed lifetimes. We propose that channels phosphorylated to 75% of maximum at serine-2809 occupy a natural low point in the
RyR2 activity landscape. This optimizes channel control, which can be accomplished either by enhanced or decreased phosphorylation, making the channel particularly sensitive to the
kinase:
phosphatase balance. Pathological situations such as
heart failure might upset this balance and thereby permit prolonged stoichiometric phosphorylation of serine-2809, which would be required for dysregulation of SR Ca(2+) release.