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Article: Both EGFR kinase and Src-related tyrosine kinases regulate human ether-à-go-go-related gene potassium channels

TitleBoth EGFR kinase and Src-related tyrosine kinases regulate human ether-à-go-go-related gene potassium channels
Authors
Issue Date2008
PublisherElsevier Inc. The Journal's web site is located at http://www.elsevier.com/locate/cellsig
Citation
Cellular Signalling, 2008, v. 20 n. 10, p. 1815-1821 How to Cite?
AbstractHuman ether-à-go-go-related gene (hERG or Kv11.1) encodes the rapidly activated delayed rectifier K+ current (IKr) in the human heart. Potential regulation of hERG channel by protein tyrosine kinases (PTKs) is not understood. The present study was designed to investigate whether this channel is modulated by PTKs using whole-cell patch clamp technique, and immunoprecipitation and Western blot analysis in HEK 293 cells stably expressing hERG gene. We found that the broad-spectrum PTK inhibitor genistein (30 μM), the selective EGFR (epidermal growth factor receptor) kinase inhibitor AG556 (10 μM) and the Src-family kinase inhibitor PP2 (10 μM) remarkably inhibited hERG channel current (IhERG), and the effects were significantly countered by the protein tyrosine phosphatase (PTP) inhibitor orthovanadate (1 mM). Immunoprecipitation and Western blot analysis demonstrated that membrane protein tyrosine phosphorylation of hERG channels was reduced by genistein, AG556, and PP2. The reduction of hERG channel phosphorylation level by genistein, AG556 or PP2 was antagonized by orthovanadate. Single point mutation(s) of Y475A and/or Y611A dramatically attenuated the inhibitory effect of IhERG by PP2 and/or AG556. Our results demonstrate the novel information that IhERG is modulated not only by Src-family kinases, but also by EGFR kinases. Y475 and/or Y611 are likely the preferred phosphorylation sites. Regulation of hERG channels by PTKs modifies the channel activity and thus likely alters electrophysiological properties including action potential duration and cell excitability in human heart and neurons. © 2008 Elsevier Inc. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/163195
ISSN
2015 Impact Factor: 4.191
2015 SCImago Journal Rankings: 2.289
ISI Accession Number ID
Funding AgencyGrant Number
Sun Chieh Yeh Heart Foundation of Hong Kong
University of Hong Kong
Funding Information:

The study was supported in part by a grant from Sun Chieh Yeh Heart Foundation of Hong Kong. De-Yong Zhang was supported by a postgraduate studentship of the University of Hong Kong.

References

 

DC FieldValueLanguage
dc.contributor.authorZhang, DYen_US
dc.contributor.authorWang, Yen_US
dc.contributor.authorLau, CPen_US
dc.contributor.authorTse, HFen_US
dc.contributor.authorLi, GRen_US
dc.date.accessioned2012-09-05T05:28:36Z-
dc.date.available2012-09-05T05:28:36Z-
dc.date.issued2008en_US
dc.identifier.citationCellular Signalling, 2008, v. 20 n. 10, p. 1815-1821en_US
dc.identifier.issn0898-6568en_US
dc.identifier.urihttp://hdl.handle.net/10722/163195-
dc.description.abstractHuman ether-à-go-go-related gene (hERG or Kv11.1) encodes the rapidly activated delayed rectifier K+ current (IKr) in the human heart. Potential regulation of hERG channel by protein tyrosine kinases (PTKs) is not understood. The present study was designed to investigate whether this channel is modulated by PTKs using whole-cell patch clamp technique, and immunoprecipitation and Western blot analysis in HEK 293 cells stably expressing hERG gene. We found that the broad-spectrum PTK inhibitor genistein (30 μM), the selective EGFR (epidermal growth factor receptor) kinase inhibitor AG556 (10 μM) and the Src-family kinase inhibitor PP2 (10 μM) remarkably inhibited hERG channel current (IhERG), and the effects were significantly countered by the protein tyrosine phosphatase (PTP) inhibitor orthovanadate (1 mM). Immunoprecipitation and Western blot analysis demonstrated that membrane protein tyrosine phosphorylation of hERG channels was reduced by genistein, AG556, and PP2. The reduction of hERG channel phosphorylation level by genistein, AG556 or PP2 was antagonized by orthovanadate. Single point mutation(s) of Y475A and/or Y611A dramatically attenuated the inhibitory effect of IhERG by PP2 and/or AG556. Our results demonstrate the novel information that IhERG is modulated not only by Src-family kinases, but also by EGFR kinases. Y475 and/or Y611 are likely the preferred phosphorylation sites. Regulation of hERG channels by PTKs modifies the channel activity and thus likely alters electrophysiological properties including action potential duration and cell excitability in human heart and neurons. © 2008 Elsevier Inc. All rights reserved.en_US
dc.languageengen_US
dc.publisherElsevier Inc. The Journal's web site is located at http://www.elsevier.com/locate/cellsigen_US
dc.relation.ispartofCellular Signallingen_US
dc.subject.meshCell Lineen_US
dc.subject.meshEther-A-Go-Go Potassium Channels - Metabolismen_US
dc.subject.meshGenistein - Pharmacologyen_US
dc.subject.meshHumansen_US
dc.subject.meshIon Channel Gating - Drug Effectsen_US
dc.subject.meshPhosphotyrosine - Metabolismen_US
dc.subject.meshPoint Mutation - Geneticsen_US
dc.subject.meshPyrimidines - Pharmacologyen_US
dc.subject.meshReceptor, Epidermal Growth Factor - Antagonists & Inhibitors - Metabolismen_US
dc.subject.meshTyrphostins - Pharmacologyen_US
dc.subject.meshVanadates - Pharmacologyen_US
dc.subject.meshSrc-Family Kinases - Metabolismen_US
dc.titleBoth EGFR kinase and Src-related tyrosine kinases regulate human ether-à-go-go-related gene potassium channelsen_US
dc.typeArticleen_US
dc.identifier.emailTse, HF:hftse@hkucc.hku.hken_US
dc.identifier.emailLi, GR:grli@hkucc.hku.hken_US
dc.identifier.authorityTse, HF=rp00428en_US
dc.identifier.authorityLi, GR=rp00476en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1016/j.cellsig.2008.06.006en_US
dc.identifier.pmid18617000-
dc.identifier.scopuseid_2-s2.0-49749147563en_US
dc.identifier.hkuros146212-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-49749147563&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume20en_US
dc.identifier.issue10en_US
dc.identifier.spage1815en_US
dc.identifier.epage1821en_US
dc.identifier.isiWOS:000259422600013-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridZhang, DY=24588358100en_US
dc.identifier.scopusauthoridWang, Y=7601492022en_US
dc.identifier.scopusauthoridLau, CP=7401968501en_US
dc.identifier.scopusauthoridTse, HF=7006070805en_US
dc.identifier.scopusauthoridLi, GR=7408462932en_US

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