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J. Biol. Chem., Vol. 279, Issue 30, 31357-31364, July 23, 2004

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Spatial and Temporal Regulation of RACK1 Function and N-methyl-D-aspartate Receptor Activity through WD40 Motif-mediated Dimerization^*

Claire Thornton, Ka-Choi Tang, Khanhky Phamluong, Ken Luong, Alicia Vagts, Donna Nikanjam, Rami Yaka¶, and Dorit Ron||**

From the Ernest Gallo Research Center, Emeryville, California, 94608, and the ^||Department of Neurology, University of California San Francisco, San Francisco, California, 94143-0114

Efficient signaling requires accurate spatial and temporal compartmentalization of proteins. RACK1 is a scaffolding protein that fulfils this role through interaction of binding partners with one of its seven WD40 domains. We recently identified the kinase Fyn and the NR2B subunit of the N-methyl-D-Aspartate receptor (NMDAR) as binding partners of RACK1. Scaffolding of Fyn near its substrate NR2B by RACK1 inhibits Fyn phosphorylation of NR2B and thereby negatively regulates channel function. We found that Fyn and NR2B share the same binding site on RACK1; however, their binding to RACK1 is not mutually exclusive (Yaka, R., Thornton, C., Vagts, A. J., Phamluong, K., Bonci, A., and Ron, D. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 5710–5715). We therefore tested the hypothesis that RACK1 forms a homodimer that allows the simultaneous binding of Fyn and NR2B. We found that RACK1 binds to itself both in vitro and in the brain. Deletion analyses identified a RACK1-RACK1 dimer-binding site within the 4th WD40 repeat, and application of the 4th WD40 repeat or a peptide derivative to hippocampal slices inhibited NMDAR activity. We further found that in hippocampal slices, both RACK1 and NR2B associated with another WD40 protein, the -subunit of G protein (G), previously shown to heterodimerize with RACK1 in vitro (Dell, E. J., Connor, J., Chen, S., Stebbins, E. G., Skiba, N. P., Mochly-Rosen, D., and Hamm, H. E. (2002) J. Biol. Chem. 277, 49888–49895). However, activation of the pituitary adenylate cyclase polypeptide (1–38) G protein-coupled receptor, previously found to induce the dissociation of RACK1 from the NMDAR complex (Yaka, R., He, D. Y., Phamluong, K., and Ron, D. (2003) J. Biol. Chem. 278, 9630–9638), attenuated the association of G with RACK1 and NR2B. Based on these results, we propose that WD40-mediated homo- and heterodimerization of RACK1 mediate the formation of a transient signaling complex that includes the NMDAR, a G protein and Fyn.

Received for publication, March 1, 2004 , and in revised form, May 10, 2004.

^* This work was supported by funds provided by the State of California for medical research on alcohol and substance abuse through the University of California, San Francisco (to D. R.) and by the Department of the Army, Grant DAMD17-0110740 (to D. R.) for which the United States Army Medical Research Acquisition Activity is the awarding and administering acquisition office. The content of the information represented does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Current address: MRC Clinical Sciences Centre, Imperial College of Science Technology and Medicine, London, UK.

^¶ Current address: Dept. of Pharmacology, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.

^** To whom correspondence should be addressed: 5858 Horton St., Suite 200, Emeryville, CA 94608. Tel.: 510-985-3150; Fax: 510-985-3101; E-mail: dorit{at}itsa.ucsf.edu.

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