Phosphorylation-dependent regulation of ryanodine receptors: A novel role for leucine/isoleucine zippers

Ryanodine receptors (RyRs), intracellular calcium release channels required for cardiac and skeletal muscle contraction, are macromolecular complexes that include kinases and phosphatases. Phosphorylation/dephosphorylation pl ays a key role in regulating the function of many ion channels, including R yRs. However, the mechanism by which kinases and phosphatases are targeted to ion channels is not well understood. We have identified a novel mechanis m involved in the formation of ion channel macromolecular complexes: kinase and phosphatase targeting proteins binding to ion channels via leucine/iso leucine zipper (LZ) motifs. Activation of kinases and phosphatases bound to RyR2 via LZs regulates phosphorylation of the channel, and disruption of k inase binding via LZ motifs prevents phosphorylation of RyR2, Elucidation o f this new role for LZs in ion channel macromolecular complexes now permits : (a) rapid mapping of kinase and phosphatase targeting protein binding sit es on ion channels; (b) predicting which kinases and phosphatases are likel y to regulate a given ion channel; (c) rapid identification of novel kinase and phosphatase targeting proteins; and (d) tools for dissecting the role of kinases and phosphatases as modulators of ion channel function.