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The Journal of Neuroscience, January 15, 2003, 23(2):392-402

A Role for the Juxtamembrane Domain of -Dystroglycan in Agrin-Induced Acetylcholine Receptor Clustering

Joanna Kahl¹ and James T. Campanelli^{1, 2}

¹ Department of Biochemistry and ² Beckman Institute and Neuroscience Program, University of Illinois, Urbana, Illinois 61801

Synaptic differentiation results from an exchange of informational molecules between synaptic partners during development. At the vertebrate neuromuscular junction, agrin is one molecule presented by the presynaptic motor neuron that plays an instructive role in postsynaptic differentiation of the muscle cell, most notably in aggregation of acetylcholine receptors (AChRs). Although agrin is the best-characterized synaptogenic molecule, its mechanism of action remains uncertain, but clearly, it requires the receptor tyrosine kinase MuSK (muscle-specific kinase), the intracellular protein rapsyn, an Src-like kinase, and cytoskeletal components. In addition, the transmembrane protein dystroglycan interacts with the cytoskeleton and is implicated in agrin responsiveness. This - heterodimer can bind agrin via its extracellular  subunit and associates with the membrane cytoskeleton via its  subunit. In this study, we demonstrate that overexpression of the  subunit of dystroglycan in cultured muscle cells inhibits agrin-induced AChR clustering. Deletion analysis and point mutagenesis demonstrate that the inhibition is mediated by an intracellular, juxtamembrane region composed of basic amino acids. Finally, the inhibition mediated by -dystroglycan extends to the minimal agrin fragment required for AChR clustering, suggesting that dystroglycan plays an important role in postsynaptic differentiation in response to agrin.

Key words: agrin; dystroglycan; juxtamembrane; acetylcholine receptor; dystrophin; neuromuscular junction

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Copyright © 2003 Society for Neuroscience  0270-6474/03/232392-11$05.00/0

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