Phosphoinositide 3‐kinase acts through RAC and Cdc42 during agrin‐induced acetylcholine receptor clustering

The formation of the neuromuscular junction (NMJ) is regulated by the nerve‐derived heparan sulfate proteoglycan agrin and the muscle‐specific kinase MuSK. Agrin induces a signal transduction pathway via MuSK, which promotes the reorganization of the postsynaptic muscle membrane. Activation of MuSK...

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Published in:Developmental neurobiology (Hoboken, N.J.) N.J.), 2007-07, Vol.67 (8), p.1047-1058
Main Authors: Nizhynska, Viktoria, Neumueller, Ralph, Herbst, Ruth
Format: Article
Language:English
Subjects:
acetylcholine receptors
agrin
Agrin - physiology
Animals
cdc42 GTP-Binding Protein - physiology
Immunohistochemistry
Mice
Muscle, Skeletal - cytology
Muscle, Skeletal - physiology
MuSK
Myoblasts - physiology
neuromuscular junction
Phosphatidylinositol 3-Kinases - metabolism
phosphoinositide 3‐kinase
rac GTP-Binding Proteins - physiology
Rats
Receptors, Cholinergic - physiology
Signal Transduction
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Summary:The formation of the neuromuscular junction (NMJ) is regulated by the nerve‐derived heparan sulfate proteoglycan agrin and the muscle‐specific kinase MuSK. Agrin induces a signal transduction pathway via MuSK, which promotes the reorganization of the postsynaptic muscle membrane. Activation of MuSK leads to the phosphorylation and redistribution of acetylcholine receptors (AChRs) and other postsynaptic proteins to synaptic sites. The accumulation of high densities of AChRs at postsynaptic regions represents a hallmark of NMJ formation and is required for proper NMJ function. Here we show that phosphoinositide 3‐kinase (PI3‐K) represents a component of the agrin/MuSK signaling pathway. Muscle cells treated with specific PI3‐K inhibitors are unable to form full‐size AChR clusters in response to agrin and AChR phosphorylation is reduced. Moreover, agrin‐induced activation of Rac and Cdc42 is impaired in the presence of PI3‐K inhibitors. PI3‐K is localized to the postsynaptic muscle membrane consistent with a role during agrin/MuSK signaling. These results put PI3‐K downstream of MuSK as regulator of AChR phosphorylation and clustering. Its role during agrin‐stimulated Rac and Cdc42 activation suggests a critical function during cytoskeletal reorganizations, which lead to the redistribution of actin‐anchored AChRs. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007.
ISSN:1932-8451
1932-846X
DOI:10.1002/dneu.20371