Regulation of ryanodine receptors via macromolecular complexes: a novel role for leucine/isoleucine zippers.

Defective calcium (Ca(2+)) signaling, manifest as a loss of excitation-contraction (EC) coupling gain in cardiac muscle, likely plays an important role in the pathophysiology of human heart failure. The mechanism underlying this loss of cardiac EC coupling gain involves altered regulation of the cardiac ryanodine receptor (RyR2), the major sarcoplasmic reticulum Ca(2+) release channel in the heart. This altered regulation of RyR2 is due, in part, to hyperphosphorylation of the channel by cyclic adenosine monophosphate-dependent protein kinase A (PKA). PKA phosphorylation of RyR2 is controlled by a macromolecular signaling complex that targets PKA and two phosphatases (PP1 and PP2A) to the channel. The targeting of PKA, PP1, and PP2A to RyR2 is dependent on the binding of targeting proteins to the channel via highly conserved leucine/isoleucine zippers (LIZs). Formation of an ion channel macromolecular signaling complex is a novel role of LIZs. Recognition of this new function for LIZ motifs has provided a road map for rapidly identifying components of the RyR2 macromolecular signaling complex that play a key role in regulating normal cardiac physiology as part of the "fight or flight" response. The components of the RyR2 macromolecular signaling complex are also novel targets for heart failure and cardiac arrhythmia therapeutics.