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Regulation of muscle acetylcholine receptor turnover by β subunit tyrosine phosphorylation.
MedLine Citation:
PMID:  23325468     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
At the neuromuscular junction (NMJ), the postsynaptic localization of muscle acetylcholine receptor (AChR) is regulated by neural signals and occurs via several processes including metabolic stabilization of the receptor. However, the molecular mechanisms that influence receptor stability remain poorly defined. Here, we show that neural agrin and the tyrosine phosphatase inhibitor, pervanadate slow the degradation of surface receptor in cultured muscle cells. Their action is mediated by tyrosine phosphorylation of the AChR?β subunit, as agrin and pervandate had no effect on receptor half-life in AChR-β(3F/3F) muscle cells, which have targeted mutations of the β subunit cytoplasmic tyrosines. Moreover, in wild type AChR-β(3Y) muscle cells, we found a linear relationship between average receptor half-life and the percentage of AChR with phosphorylated β subunit, with half-lives of 12.7 and 23 hours for non-phosphorylated and phosphorylated receptor, respectively. Surprisingly, pervanadate increased receptor half-life in AChR-β(3Y) myotubes in the absence of clustering, and agrin failed to increase receptor half-life in AChR-β(3F/3F) myotubes even in the presence of clustering. The metabolic stabilization of the AChR was mediated specifically by phosphorylation of βY390 as mutation of this residue abolished β subunit phosphorylation but did not affect δ subunit phosphorylation. Receptor stabilization also led to higher receptor levels, as agrin increased surface AChR by 30% in AChR-β(3Y) but not AChR-β(3F/3F) myotubes. Together, these findings identify an unexpected role for agrin-induced phosphorylation of β(Y390) in down-regulating AChR turnover. This likely stabilizes AChR at developing synapses, and contributes to the extended half-life of AChR at adult NMJs. © 2013 Wiley Periodicals, Inc. Develop Neurobiol, 2013.
Authors:
Jb Rudell; Mj Ferns
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-16
Journal Detail:
Title:  Developmental neurobiology     Volume:  -     ISSN:  1932-846X     ISO Abbreviation:  Dev Neurobiol     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-17     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101300215     Medline TA:  Dev Neurobiol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2013 Wiley Periodicals, Inc.
Affiliation:
Depts of Physiology and Membrane Biology Davis, CA.
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