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Article: Modulation of human cardiac transient outward potassium current by EGFR tyrosine kinase and Src-family kinases
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TitleModulation of human cardiac transient outward potassium current by EGFR tyrosine kinase and Src-family kinases
 
AuthorsZhang, YH1
Wu, W1
Sun, HY1
Deng, XL2
Cheng, LC1
Li, X1
Tse, HF1
Lau, CP1
Li, GR1
 
KeywordsEGFR kinase
hKv4.3
Human atrial myocytes
Protein tyrosine kinases
Protein tyrosine phosphatase
Src-family kinases
Transient outward potassium current
 
Issue Date2012
 
PublisherOxford University Press. The Journal's web site is located at http://cardiovascres.oxfordjournals.org
 
CitationCardiovascular Research, 2012, v. 93 n. 3, p. 424-433 [How to Cite?]
DOI: http://dx.doi.org/10.1093/cvr/cvr347
 
AbstractAims: The human cardiac transient outward K + current Ito (encoded by Kv4.3 or KCND3) plays an important role in phase 1 rapid repolarization of cardiac action potentials in the heart. However, modulation of I to by intracellular signal transduction is not fully understood. The present study was therefore designed to determine whether/how human atrial I to and hKv4.3 channels stably expressed in HEK 293 cells are regulated by protein tyrosine kinases (PTKs). Methods and results: Whole-cell patch voltage-clamp, immunoprecipitation, western blotting, and site-directed mutagenesis approaches were employed in the present study. We found that human atrial I to was inhibited by the broad-spectrum PTK inhibitor genistein, the selective epidermal growth factor receptor (EGFR) kinase inhibitor AG556, and the Src-family kinases inhibitor PP2. The inhibitory effect was countered by the protein tyrosine phosphatase inhibitor orthovanadate. In HEK 293 cells stably expressing human KCND3, genistein, AG556, and PP2 significantly reduced the hKv4.3 current, and the reduction was antagonized by orthovanadate. Interestingly, orthovanadate also reversed the reduced tyrosine phosphorylation level of hKv4.3 channels by genistein, AG556, or PP2. Mutagenesis revealed that the hKv4.3 mutant Y136F lost the inhibitory response to AG556, while Y108F lost response to PP2. The double-mutant Y108FY136F hKv4.3 channels showed no response to either AG556 or PP2. Conclusion: Our results demonstrate that human atrial Ito and cloned hKv4.3 channels are modulated by EGFR kinase via phosphorylation of the Y136 residue and by Src-family kinases via phosphorylation of the Y108 residue; tyrosine phosphorylation of the channel may be involved in regulating cardiac electrophysiology. © The Author 2011.
 
ISSN0008-6363
2012 Impact Factor: 5.94
2012 SCImago Journal Rankings: 2.219
 
DOIhttp://dx.doi.org/10.1093/cvr/cvr347
 
ISI Accession Number IDWOS:000300789300009
Funding AgencyGrant Number
Sun Chieh Yeh Heart Foundation of Hong Kong
University of Hong Kong
Funding Information:

The work was supported in part by a grant from Sun Chieh Yeh Heart Foundation of Hong Kong. Y.H.Z. and W.W. were supported by a post-graduate scholarship from the University of Hong Kong.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorZhang, YH
 
dc.contributor.authorWu, W
 
dc.contributor.authorSun, HY
 
dc.contributor.authorDeng, XL
 
dc.contributor.authorCheng, LC
 
dc.contributor.authorLi, X
 
dc.contributor.authorTse, HF
 
dc.contributor.authorLau, CP
 
dc.contributor.authorLi, GR
 
dc.date.accessioned2012-02-03T06:13:38Z
 
dc.date.available2012-02-03T06:13:38Z
 
dc.date.issued2012
 
dc.description.abstractAims: The human cardiac transient outward K + current Ito (encoded by Kv4.3 or KCND3) plays an important role in phase 1 rapid repolarization of cardiac action potentials in the heart. However, modulation of I to by intracellular signal transduction is not fully understood. The present study was therefore designed to determine whether/how human atrial I to and hKv4.3 channels stably expressed in HEK 293 cells are regulated by protein tyrosine kinases (PTKs). Methods and results: Whole-cell patch voltage-clamp, immunoprecipitation, western blotting, and site-directed mutagenesis approaches were employed in the present study. We found that human atrial I to was inhibited by the broad-spectrum PTK inhibitor genistein, the selective epidermal growth factor receptor (EGFR) kinase inhibitor AG556, and the Src-family kinases inhibitor PP2. The inhibitory effect was countered by the protein tyrosine phosphatase inhibitor orthovanadate. In HEK 293 cells stably expressing human KCND3, genistein, AG556, and PP2 significantly reduced the hKv4.3 current, and the reduction was antagonized by orthovanadate. Interestingly, orthovanadate also reversed the reduced tyrosine phosphorylation level of hKv4.3 channels by genistein, AG556, or PP2. Mutagenesis revealed that the hKv4.3 mutant Y136F lost the inhibitory response to AG556, while Y108F lost response to PP2. The double-mutant Y108FY136F hKv4.3 channels showed no response to either AG556 or PP2. Conclusion: Our results demonstrate that human atrial Ito and cloned hKv4.3 channels are modulated by EGFR kinase via phosphorylation of the Y136 residue and by Src-family kinases via phosphorylation of the Y108 residue; tyrosine phosphorylation of the channel may be involved in regulating cardiac electrophysiology. © The Author 2011.
 
dc.description.naturepostprint
 
dc.identifier.citationCardiovascular Research, 2012, v. 93 n. 3, p. 424-433 [How to Cite?]
DOI: http://dx.doi.org/10.1093/cvr/cvr347
 
dc.identifier.doihttp://dx.doi.org/10.1093/cvr/cvr347
 
dc.identifier.eissn1755-3245
 
dc.identifier.epage433
 
dc.identifier.hkuros198242
 
dc.identifier.isiWOS:000300789300009
Funding AgencyGrant Number
Sun Chieh Yeh Heart Foundation of Hong Kong
University of Hong Kong
Funding Information:

The work was supported in part by a grant from Sun Chieh Yeh Heart Foundation of Hong Kong. Y.H.Z. and W.W. were supported by a post-graduate scholarship from the University of Hong Kong.

 
dc.identifier.issn0008-6363
2012 Impact Factor: 5.94
2012 SCImago Journal Rankings: 2.219
 
dc.identifier.issue3
 
dc.identifier.pmid22198508
 
dc.identifier.scopuseid_2-s2.0-84863276532
 
dc.identifier.spage424
 
dc.identifier.urihttp://hdl.handle.net/10722/144554
 
dc.identifier.volume93
 
dc.languageeng
 
dc.publisherOxford University Press. The Journal's web site is located at http://cardiovascres.oxfordjournals.org
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofCardiovascular Research
 
dc.relation.referencesReferences in Scopus
 
dc.rightsThis is a pre-copy-editing, author-produced PDF of an article accepted for publication in Cardiovascular Research following peer review. The definitive publisher-authenticated version Cardiovascular Research, 2012, v. 93 n. 3, p. 424-433 is available online at: http://cardiovascres.oxfordjournals.org/content/93/3/424
 
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License
 
dc.subjectEGFR kinase
 
dc.subjecthKv4.3
 
dc.subjectHuman atrial myocytes
 
dc.subjectProtein tyrosine kinases
 
dc.subjectProtein tyrosine phosphatase
 
dc.subjectSrc-family kinases
 
dc.subjectTransient outward potassium current
 
dc.titleModulation of human cardiac transient outward potassium current by EGFR tyrosine kinase and Src-family kinases
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
  2. Xi'an Jiaotong University, School of Medicine