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Article: Genistein and tyrphostin AG556 inhibit inwardly-rectifying Kir2.1 channels expressed in HEK 293 cells via protein tyrosine kinase inhibition

TitleGenistein and tyrphostin AG556 inhibit inwardly-rectifying Kir2.1 channels expressed in HEK 293 cells via protein tyrosine kinase inhibition
Authors
KeywordsEpidermal growth factor receptor kinase
Inward rectifier K + channel
Kir2.1
Protein tyrosine kinase
Issue Date2011
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/bbamem
Citation
Biochimica Et Biophysica Acta - Biomembranes, 2011, v. 1808 n. 8, p. 1993-1999 How to Cite?
AbstractPrevious studies reported the controversial effects that protein tyrosine kinase (PTK) inhibition could induce an up-regulation or down-regulation of Kir2.1 current. The present study investigates how the recombinant human Kir2.1 channels are regulated by PTKs using whole-cell patch voltage-clamp, immunoprecipitation and Western blot, and mutagenesis approaches. We found that hKir2.1 current was reversibly inhibited by the broad spectrum PTK inhibitor genistein and the highly selective EGFR (epidermal growth factor receptor) kinase inhibitor AG556 in a concentration-dependent manner. The inhibition of hKir2.1 channels by genistein or AG556 was countered by the protein tyrosine phosphatase (PTP) inhibitor orthovanadate. Immunoprecipitation and Western blot analysis revealed that tyrosine phosphorylation level of Kir2.1 channels was reduced by genistein or AG556, and the reduction was significantly antagonized by orthovanadate. The mutation of Y242 dramatically reduced the inhibitory response to AG556. The results obtained in this study demonstrate that hKir2.1 channels are down-regulated by PTK inhibition, suggesting that EGFR kinase participates in the modulation of human cardiac excitability. © 2011 Elsevier B.V.
Persistent Identifierhttp://hdl.handle.net/10722/137402
ISSN
2015 Impact Factor: 3.687
2015 SCImago Journal Rankings: 1.769
ISI Accession Number ID
Funding AgencyGrant Number
Research Grant Council of Hong Kong760306M
Sun Chieh Yeh Heart Foundation of Hong Kong
University of Hong Kong
Funding Information:

The study was supported in part by the General Research Fund 760306M from Research Grant Council of Hong Kong and a grant from Sun Chieh Yeh Heart Foundation of Hong Kong. De-Yong Zhang and Wei Wu are supported by a postgraduate studentship from the University of Hong Kong. The authors thank Ms Hai-Ying Sun for the excellent technical support, and Dr. Carol A. Vandenberg (University of California, Santa Barbara, CA) for generously providing us the hKir2.1 plasmid vector.

References

 

DC FieldValueLanguage
dc.contributor.authorZhang, DYen_HK
dc.contributor.authorWu, Wen_HK
dc.contributor.authorDeng, XLen_HK
dc.contributor.authorLau, CPen_HK
dc.contributor.authorLi, GRen_HK
dc.date.accessioned2011-08-26T14:24:25Z-
dc.date.available2011-08-26T14:24:25Z-
dc.date.issued2011en_HK
dc.identifier.citationBiochimica Et Biophysica Acta - Biomembranes, 2011, v. 1808 n. 8, p. 1993-1999en_HK
dc.identifier.issn0005-2736en_HK
dc.identifier.urihttp://hdl.handle.net/10722/137402-
dc.description.abstractPrevious studies reported the controversial effects that protein tyrosine kinase (PTK) inhibition could induce an up-regulation or down-regulation of Kir2.1 current. The present study investigates how the recombinant human Kir2.1 channels are regulated by PTKs using whole-cell patch voltage-clamp, immunoprecipitation and Western blot, and mutagenesis approaches. We found that hKir2.1 current was reversibly inhibited by the broad spectrum PTK inhibitor genistein and the highly selective EGFR (epidermal growth factor receptor) kinase inhibitor AG556 in a concentration-dependent manner. The inhibition of hKir2.1 channels by genistein or AG556 was countered by the protein tyrosine phosphatase (PTP) inhibitor orthovanadate. Immunoprecipitation and Western blot analysis revealed that tyrosine phosphorylation level of Kir2.1 channels was reduced by genistein or AG556, and the reduction was significantly antagonized by orthovanadate. The mutation of Y242 dramatically reduced the inhibitory response to AG556. The results obtained in this study demonstrate that hKir2.1 channels are down-regulated by PTK inhibition, suggesting that EGFR kinase participates in the modulation of human cardiac excitability. © 2011 Elsevier B.V.en_HK
dc.languageengen_US
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/bbamemen_HK
dc.relation.ispartofBiochimica et Biophysica Acta - Biomembranesen_HK
dc.subjectEpidermal growth factor receptor kinaseen_HK
dc.subjectInward rectifier K + channelen_HK
dc.subjectKir2.1en_HK
dc.subjectProtein tyrosine kinaseen_HK
dc.subject.meshGenistein - pharmacology-
dc.subject.meshPotassium Channels, Inwardly Rectifying - antagonists and inhibitors - genetics - metabolism-
dc.subject.meshProtein Kinase Inhibitors - pharmacology-
dc.subject.meshProtein-Tyrosine Kinases - antagonists and inhibitors - metabolism-
dc.subject.meshTyrphostins - pharmacology-
dc.titleGenistein and tyrphostin AG556 inhibit inwardly-rectifying Kir2.1 channels expressed in HEK 293 cells via protein tyrosine kinase inhibitionen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0006-3002 (Print)0006-3002 (Linking)&volume=1808&issue=8&spage=1993&epage=9&date=2011&atitle=Genistein+and+tyrphostin+AG556+inhibit+inwardly-rectifying+Kir2.1+channels+expressed+in+HEK+293+cells+via+protein+tyrosine+kinase+inhibitionen_US
dc.identifier.emailLi, GR:grli@hkucc.hku.hken_HK
dc.identifier.authorityLi, GR=rp00476en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.bbamem.2011.04.015en_HK
dc.identifier.pmid21570948-
dc.identifier.scopuseid_2-s2.0-79958157096en_HK
dc.identifier.hkuros190717en_US
dc.identifier.hkuros186208-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79958157096&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume1808en_HK
dc.identifier.issue8en_HK
dc.identifier.spage1993en_HK
dc.identifier.epage1999en_HK
dc.identifier.isiWOS:000292350300005-
dc.publisher.placeNetherlandsen_HK
dc.identifier.scopusauthoridZhang, DY=24588358100en_HK
dc.identifier.scopusauthoridWu, W=43161580300en_HK
dc.identifier.scopusauthoridDeng, XL=14057894600en_HK
dc.identifier.scopusauthoridLau, CP=7401968501en_HK
dc.identifier.scopusauthoridLi, GR=7408462932en_HK
dc.identifier.citeulike9278687-

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