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The Journal of Neuroscience, November 5, 2008, 28(45):11468-11476; doi:10.1523/JNEUROSCI.2508-08.2008

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Cellular/Molecular
Identification of a Motif in the Acetylcholine Receptor β Subunit Whose Phosphorylation Regulates Rapsyn Association and Postsynaptic Receptor Localization

Lucia S. Borges,^1 * Sergey Yechikhov,^1 * Young I. Lee,¹ John B. Rudell,¹ Matthew B. Friese,² Steven J. Burden,² and Michael J. Ferns¹

¹Departments of Anesthesiology and Physiology and Membrane Biology, University of California, Davis, Davis, California 95616, and ²Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, New York University Medical School, New York, New York 10016

Correspondence should be addressed to Dr. Michael J. Ferns, Department of Physiology and Membrane Biology, University of California, Davis, One Shields Avenue, Davis, CA 95616. Email: mjferns{at}ucdavis.edu

At the neuromuscular junction, the acetylcholine receptor (AChR) is specifically clustered in the postsynaptic membrane via interactions with rapsyn and other scaffolding proteins. However, it remains unclear where these proteins bind on the AChR and how the interactions are regulated. Here, we define a phosphorylation-dependent binding site on the receptor that mediates agrin-induced clustering. Using chimeric proteins in which CD4 is fused to the large intracellular loop of each of the AChR subunits we found that agrin induced clustering of only chimeras containing the β subunit loop. By making deletions in the β loop we defined a 20 amino-acid sequence that is sufficient for clustering. The sequence contains a conserved tyrosine (Y390) whose phosphorylation is induced by agrin and whose mutation abolished clustering of β loop chimeras and their ability to inhibit agrin-induced clustering of the endogenous AChR. Phosphorylation of the AChR β subunit is correlated with increased rapsyn/AChR binding, suggesting that the effect of βY390 phosphorylation on clustering is mediated by rapsyn. Indeed, we found that rapsyn associated with CD4-β loop chimeras in a phosphorylation-dependent manner, and that agrin increased the ratio of rapsyn binding to wild type AChR but not to AChR-β^3F/3F, which lacks β loop tyrosine phosphorylation sites. Together, these findings suggest that agrin-induced phosphorylation of the β subunit motif increases the stoichiometry of rapsyn binding to the AChR, thereby helping to stably cluster the receptor and anchor it at high density in the postsynaptic membrane.

Key words: synaptogenesis; neuromuscular junction; nicotinic acetylcholine receptor; phosphorylation; postsynaptic membrane; agrin

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Received June 3, 2008; revised Sept. 10, 2008; accepted Sept. 22, 2008.

Correspondence should be addressed to Dr. Michael J. Ferns, Department of Physiology and Membrane Biology, University of California, Davis, One Shields Avenue, Davis, CA 95616. Email: mjferns{at}ucdavis.edu

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