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J. Cell Biol. 153 (4): 699-708

Copyright © 2001 by the Rockefeller University Press.

Original Article

Phosphorylation-Dependent Regulation of Ryanodine Receptors

A Novel Role for Leucine/Isoleucine Zippers

Steven O. Marxa, Steven Reikena, Yuji Hisamatsua, Marta Gaburjakovaa, Jana Gaburjakovaa, Yi-Ming Yanga, Nora Rosemblita, , and Andrew R. Marksa

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


Abstract: 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

Abbreviations used in this paper: aa, amino acid(s); EC, excitation–contraction; FKBP, FK506 binding protein; GST, glutathione S-transferase; IP3R, inositol 1,4,5 trisphosphate receptor; LZ, leucine/isoleucine zipper; mAKAP, muscle A-kinase anchoring protein; PKA, protein kinase A; PKI, protein kinase inhibitor; PP, protein phosphatase; RyR, ryanodine receptor; SR, sarcoplasmic reticulum.

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