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Tyrosine 284 phosphorylation is required for ClC-3 chloride channel activation in vascular smooth muscle cells.
MedLine Citation:
PMID:  23536605     Owner:  NLM     Status:  Publisher    
AIMS: ClC-3 chloride channel (ICl.ClC-3) plays an important role in cell volume regulation, proliferation, apoptosis in vascular smooth muscle cells, and is a potential target for prevention of vascular remodeling and stroke. However, modulation of ICl.ClC-3 by intercellular signaling is not fully understood. Although it has been suggested that tyrosine phosphorylation is required for ICl.ClC-3 activation, the potential tyrosine residues in ClC-3 protein are not clear. The present study is to investigate critical tyrosine residues in ClC-3 protein. METHODS AND RESULTS: Site-specific mutagenesis, immunoprecipitation, patch clamp and Cl(-) transport imaging techniques were employed in this study. We found that activation of ICl.ClC-3 was associated with tyrosine phosphorylation in ClC-3 protein. Three potential tyrosine residues, Y284, Y572 and Y631, were mutated to phenylalanine, and only mutation at Y284 within a consensus Src-phosphorylation site completely blocked ICl.ClC-3. Phosphomimitetic mutation Y284D increased Cl(-) current and Cl(-) efflux mediated by ClC-3. Y284F mutation completely abolished ClC-3 protective effect on apoptosis, whereas Y284D mutation potentiated it. There was an interaction between Src kinase and ClC-3 protein, and Y284D mutation abrogated the inhibitory effect of SU6656, a Src family kinase inhibitor, on ClC-3 Cl(-) current. CONCLUSION: Tyrosine 284 phosphorylation in ClC-3 channel targeted by Src kinase is an important molecular mechanism for ClC-3 channel activation.
Xiao-Guang Wang; Jing Tao; Ming-Ming Ma; Yong-Bo Tang; Jia-Guo Zhou; Yong-Yuan Guan
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-3-27
Journal Detail:
Title:  Cardiovascular research     Volume:  -     ISSN:  1755-3245     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-3-28     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Department of Pharmacology, Cardiac & Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University.
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