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Article: Modulation of human cardiac transient outward potassium current by EGFR tyrosine kinase and Src-family kinases

TitleModulation of human cardiac transient outward potassium current by EGFR tyrosine kinase and Src-family kinases
Authors
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
Citation
Cardiovascular Research, 2012, v. 93 n. 3, p. 424-433 How to Cite?
Abstract
Aims: 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.
Persistent Identifierhttp://hdl.handle.net/10722/144554
ISSN
2013 Impact Factor: 5.808
2013 SCImago Journal Rankings: 2.799
ISI Accession Number ID
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.

References

 

DC FieldValueLanguage
dc.contributor.authorZhang, YHen_HK
dc.contributor.authorWu, Wen_HK
dc.contributor.authorSun, HYen_HK
dc.contributor.authorDeng, XLen_HK
dc.contributor.authorCheng, LCen_HK
dc.contributor.authorLi, Xen_HK
dc.contributor.authorTse, HFen_HK
dc.contributor.authorLau, CPen_HK
dc.contributor.authorLi, GRen_HK
dc.date.accessioned2012-02-03T06:13:38Z-
dc.date.available2012-02-03T06:13:38Z-
dc.date.issued2012en_HK
dc.identifier.citationCardiovascular Research, 2012, v. 93 n. 3, p. 424-433en_HK
dc.identifier.issn0008-6363en_HK
dc.identifier.urihttp://hdl.handle.net/10722/144554-
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.en_HK
dc.languageengen_US
dc.publisherOxford University Press. The Journal's web site is located at http://cardiovascres.oxfordjournals.orgen_HK
dc.relation.ispartofCardiovascular Researchen_HK
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 kinaseen_HK
dc.subjecthKv4.3en_HK
dc.subjectHuman atrial myocytesen_HK
dc.subjectProtein tyrosine kinasesen_HK
dc.subjectProtein tyrosine phosphataseen_HK
dc.subjectSrc-family kinasesen_HK
dc.subjectTransient outward potassium currenten_HK
dc.titleModulation of human cardiac transient outward potassium current by EGFR tyrosine kinase and Src-family kinasesen_HK
dc.typeArticleen_HK
dc.identifier.emailLi, GR:grli@hkucc.hku.hken_HK
dc.identifier.authorityLi, GR=rp00476en_HK
dc.description.naturepostprint-
dc.identifier.doi10.1093/cvr/cvr347en_HK
dc.identifier.pmid22198508en_HK
dc.identifier.scopuseid_2-s2.0-84863276532en_HK
dc.identifier.hkuros198242en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84863276532&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume93en_HK
dc.identifier.issue3en_HK
dc.identifier.spage424en_HK
dc.identifier.epage433en_HK
dc.identifier.eissn1755-3245-
dc.identifier.isiWOS:000300789300009-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridZhang, YH=54381132400en_HK
dc.identifier.scopusauthoridWu, W=43161580300en_HK
dc.identifier.scopusauthoridSun, HY=35723049200en_HK
dc.identifier.scopusauthoridDeng, XL=14057894600en_HK
dc.identifier.scopusauthoridCheng, LC=55278013400en_HK
dc.identifier.scopusauthoridLi, X=55278182700en_HK
dc.identifier.scopusauthoridTse, HF=54886126900en_HK
dc.identifier.scopusauthoridLau, CP=35275317200en_HK
dc.identifier.scopusauthoridLi, GR=7408462932en_HK

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