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© The Rockefeller University Press, 0021-9525/2001//699 $5.00
The Journal of Cell Biology, Volume 153, Number 4, , 2001 699-708

Phosphorylation-Dependent Regulation of Ryanodine Receptors

Steven O. Marx^a, Steven Reiken^a, Yuji Hisamatsu^a, Marta Gaburjakova^a, Jana Gaburjakova^a, Yi-Ming Yang^a, Nora Rosemblit^a, and Andrew R. Marks^a

^a Center for Molecular Cardiology, Department of Medicine, Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, New York 10032
Center for Molecular Cardiology, Box 65, Columbia University College of Physicians and Surgeons, Rm. 9-401, 630 West 168th St., New York, NY 10032.(212) 305-3690(212) 305-0270

arm42{at}columbia.edu

Ryanodine receptors (RyRs), intracellular calcium release channels required for cardiac and skeletal muscle contraction, are macromolecular complexes that include kinases and phosphatases. Phosphorylation/dephosphorylation plays a key role in regulating the function of many ion channels, including RyRs. However, the mechanism by which kinases and phosphatases are targeted to ion channels is not well understood. We have identified a novel mechanism involved in the formation of ion channel macromolecular complexes: kinase and phosphatase targeting proteins binding to ion channels via leucine/isoleucine zipper (LZ) motifs. Activation of kinases and phosphatases bound to RyR2 via LZs regulates phosphorylation of the channel, and disruption of kinase binding via LZ motifs prevents phosphorylation of RyR2. Elucidation of this new role for LZs in ion channel macromolecular complexes now permits: (a) rapid mapping of kinase and phosphatase targeting protein binding sites on ion channels; (b) predicting which kinases and phosphatases are likely 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.

Key Words: leucine zipper • ryanodine receptor • calcium channel • phosphorylation • phosphatase

© 2001 The Rockefeller University Press

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