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PNAS 101 (8): 2328-2332

Copyright © 2004 by the National Academy of Sciences.

CELL BIOLOGY

RACK1 binds to inositol 1,4,5-trisphosphate receptors and mediates Ca2+ release

Randen L. Patterson * {dagger}, Damian B. van Rossum * {dagger}, Roxanne K. Barrow *, and Solomon H. Snyder * {ddagger} § ¶

Departments of *Neuroscience, {ddagger}Pharmacology and Molecular Science, and §Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205

Contributed by Solomon H. Snyder, December 30, 2003

Abstract: RACK1 is not a G protein but closely resembles the heterotrimeric G{beta}-subunit. RACK1 serves as a scaffold, linking protein kinase C to its substrates. We demonstrate that RACK1 physiologically binds inositol 1,4,5-trisphosphate receptors and regulates Ca2+ release by enhancing inositol 1,4,5-trisphosphate receptor binding affinity for inositol 1,4,5-trisphosphate. Overexpression of RACK1 or depletion of RACK1 by interference RNA markedly augments or diminishes Ca2+ release, respectively, without affecting Ca2+ entry. These findings establish RACK1 as a physiologic mediator of agonist-induced Ca2+ release.

Abbreviations: IP3, inositol 1,4,5-trisphosphate; IP3R, IP3 receptor; G{beta}, G{beta}-subunit; siRNA, small interfering RNA; YFP, yellow fluorescent protein; aa, amino acids; HEK, human embryonic kidney.

{dagger} R.L.P. and D.B.v.R. contributed equally to this work.

To whom correspondence should be addressed at: Department of Neuroscience, Johns Hopkins University, 725 North Wolfe Street, 813 WBSB, Baltimore, MD 21205. E-mail: ssnyder{at}jhmi.edu.

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