Phosphorylation-dependent Regulation of Ryanodine Receptors: A Novel Role for Leucine/Isoleucine Zippers

doi:10.1083/jcb.153.4.699

Published online 7 May 2001. doi:10.1083/jcb.153.4.699

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© The Rockefeller University Press, 0021-9525/2001/5/699/ $5.00
The Journal of Cell Biology, Volume 153, Number 4, May 14, 2001 699-708

Original Article

Phosphorylation-dependent Regulation of Ryanodine Receptors: A Novel Role for Leucine/Isoleucine Zippers

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

Correspondence to: Andrew R. Marks, Center for Molecular Cardiology, Box 65, Columbia University College of Physicians and Surgeons, Rm. 9-401, 630 West 168th St., New York, NY 10032. Tel:(212) 305-0270 Fax:(212) 305-3690 E-mail:arm42{at}columbia.edu.

Ryanodine receptors (RyRs), intracellular calcium release channelsrequired for cardiac and skeletal muscle contraction, are macromolecularcomplexes that include kinases and phosphatases. Phosphorylation/dephosphorylationplays a key role in regulating the function of many ion channels,including RyRs. However, the mechanism by which kinases andphosphatases are targeted to ion channels is not well understood.We have identified a novel mechanism involved in the formationof ion channel macromolecular complexes: kinase and phosphatasetargeting proteins binding to ion channels via leucine/isoleucinezipper (LZ) motifs. Activation of kinases and phosphatases boundto RyR2 via LZs regulates phosphorylation of the channel, anddisruption of kinase binding via LZ motifs prevents phosphorylationof RyR2. Elucidation of this new role for LZs in ion channelmacromolecular complexes now permits: (a) rapid mapping of kinaseand phosphatase targeting protein binding sites on ion channels;(b) predicting which kinases and phosphatases are likely toregulate a given ion channel; (c) rapid identification of novelkinase and phosphatase targeting proteins; and (d) tools fordissecting the role of kinases and phosphatases as modulatorsof ion channel function.

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

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