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J. Biol. Chem., Vol. 278, Issue 9, 7350-7359, February 28, 2003
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From the The acetylcholine receptor
(AChR)-associated protein rapsyn is essential for neuromuscular synapse
formation and clustering of AChRs, but its mode of action remains
unclear. We have investigated whether agrin, a key nerve-derived
synaptogenic factor, influences rapsyn-AChR interactions and how this
affects clustering and cytoskeletal linkage of AChRs. By precipitating
AChRs and probing for associated rapsyn, we found that in denervated
diaphragm rapsyn associates with synaptic as well as with extrasynaptic
AChRs showing that rapsyn interacts with unclustered AChRs in
vivo. Interestingly, synaptic AChRs are associated with more
rapsyn suggesting that clustering of AChRs may require increased
interaction with rapsyn. In similar experiments in cultured myotubes,
rapsyn interacted with intracellular AChRs and with unclustered AChRs
at the cell surface, although surface interactions are much more
prominent. Remarkably, agrin induces recruitment of additional rapsyn
to surface AChRs and clustering of AChRs independently of the secretory pathway. This agrin-induced increase in rapsyn-AChR interaction strongly correlates with clustering, because staurosporine and herbimycin blocked both the increase and clustering. Conversely, laminin and calcium induced both increased rapsyn-AChR interaction and
AChR clustering. Finally, time course experiments revealed that the
agrin-induced increase occurs with AChRs that become cytoskeletally
linked, and that this precedes receptor clustering. Thus, we
propose that neural agrin controls postsynaptic aggregation of the AChR
by enhancing rapsyn interaction with surface AChRs and inducing
cytoskeletal anchoring and that this is an important precursor step for
AChR clustering.
Agrin Regulates Rapsyn Interaction with Surface Acetylcholine
Receptors, and This Underlies Cytoskeletal Anchoring and
Clustering*
,,,
Department of Neurochemistry, Brain Research
Institute, University of Zürich, CH-8057 Zürich,
Switzerland, the § Department of Neurology & Neurosurgery,
McGill University, Montreal, Quebec H3A 2T5, Canada, and the
¶ Department of Physiology, University of Basel, CH-4051 Basel,
Switzerland
*
This work was supported by the Dr. Eric Slack-Gyr
Foundation, the National Center of Competence in Research "Neural
Plasticity and Repair," by grants from the Swiss National Science
Foundation and the Swiss Foundation for Research on Muscle Diseases (to
C. F.), and by a Canadian Institute of Health Research grant (to M. F.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Brain Research
Inst., University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. Tel.: 41-1-635-33-10; Fax:
41-1-635-33-03; E-mail: chfuhrer@hifo.unizh.ch.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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