Inhibition of agrin-mediated acetylcholine receptor clustering by utrophin C-terminal peptides.
BACKGROUND
Agrin is an extracellular matrix protein that is required for neuromuscular synaptogenesis and is particularly important in the clustering of acetylcholine receptors at post-synaptic sites. Little is known about the signal transduction pathway of agrin-mediated receptor clustering, although cytoskeletal elements and a dystrophin associated glycoprotein complex (DGC) have been implicated. Because agrin binds to alpha-dystroglycan, a member of the DGC, and the DGC is linked to actin through utrophin at postsynaptic sites, it has been suggested that binding of utrophin to the DGC plays a central role in agrin mediated receptor clustering.


RESULTS
To test this hypothesis, we expressed at high levels the DGC binding domains of utrophin in cultured myotubes using recombinant Semliki Forest Virus. Myotubes expressing the utrophin and dystrophin DGC binding domain formed significantly fewer acetylcholine receptor clusters in response to agrin than myotubes expressing other proteins.


CONCLUSIONS
These results suggest involvement of the DGC and utrophin in the signal transduction pathway of agrin-mediated acetylcholine receptor cluster formation or stabilization.
Namba
T
T
Department of Molecular and Cellular Physiology, Stanford University Medical School, CA 94305, USA.
Scheller
R H
RH
D018171:Agrin / Q000037:antagonists & inhibitors*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003598:Cytoskeletal Proteins / Q000378:metabolism / Q000502:physiology*; D049030:Dystroglycans; D016189:Dystrophin / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D009132:Muscles; D009469:Neuromuscular Junction / Q000502:physiology; D010446:Peptide Fragments; D011485:Protein Binding; D011940:Receptor Aggregation; D011950:Receptors, Cholinergic / Q000378:metabolism*; D011994:Recombinant Proteins; D015398:Signal Transduction; D014162:Transfection; D049411:Utrophin
D018171:Agrin; D003598:Cytoskeletal Proteins; C483081:DAG1 protein, human; D016189:Dystrophin; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D011950:Receptors, Cholinergic; D011994:Recombinant Proteins; C483600:Utrn protein, mouse; D049411:Utrophin; D049030:Dystroglycans