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Article: Epidermal growth factor receptor tyrosine kinase regulates the human inward rectifier potassium K IR2.3 channel, stably expressed in HEK 293 cells

TitleEpidermal growth factor receptor tyrosine kinase regulates the human inward rectifier potassium K IR2.3 channel, stably expressed in HEK 293 cells
Authors
KeywordsEGFR tyrosine kinase
inward rectifier K + channels
protein tyrosine kinase
protein tyrosine phosphatase
tyrosine phosphorylation
Issue Date2011
PublisherJohn Wiley & Sons Ltd. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=0007-1188&site=1
Citation
British Journal Of Pharmacology, 2011, v. 164 n. 5, p. 1469-1478 How to Cite?
AbstractBackground and Purpose The detailed molecular modulation of inward rectifier potassium channels (including the K IR2.3 channel) is not fully understood. The present study was designed to determine whether human K IR2.3 (K IR2.3) channels were regulated by protein tyrosine kinases (PTKs). Experimental Approach Whole-cell patch voltage-clamp, immunoprecipitation, Western blot analysis and site-directed mutagenesis were employed to determine the potential PTK phosphorylation of Kir2.3 current in HEK 293 cells stably expressing Kir2.3 gene. Key Results The broad-spectrum PTK inhibitor genistein (10 ÂμM) and the selective epidermal growth factor (EGF) kinase inhibitor AG556 (10 ÂμM) reversibly decreased K IR2.3 current and the effect was reversed by the protein tyrosine phosphatase inhibitor, orthovanadate (1 mM). Although EGF (100 ng·mL -1) and orthovanadate enhanced K IR2.3 current, this effect was antagonized by AG556. However, the Src-family tyrosine kinase inhibitor PP2 (10 ÂμM) did not inhibit K IR2.3 current. Tyrosine phosphorylation of K IR2.3 channels was decreased by genistein or AG556, and was increased by EGF or orthovanadate. The decrease of tyrosine phosphorylation of K IR2.3 channels by genistein or AG556 was reversed by orthovanadate or EGF. Interestingly, the response of K IR2.3 channels to EGF or AG556 was lost in the K IR2.3 Y234A mutant channel. Conclusion and Implications These results demonstrate that the EGF receptor tyrosine kinase up-regulates the K IR2.3 channel via phosphorylation of the Y234 residue of the WT protein. This effect may be involved in the endogenous regulation of cellular electrical activity. © 2011 The British Pharmacological Society.
Persistent Identifierhttp://hdl.handle.net/10722/142403
ISSN
2014 Impact Factor: 4.842
2014 SCImago Journal Rankings: 1.844
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Research Grant Council of Hong KongHKU 760306 M
Sun Chieh Yeh Heart Foundation of Hong Kong
University of Hong Kong
Funding Information:

This work was supported in part by a General Research Fund (HKU 760306 M) from Research Grant Council of Hong Kong and a grant from Sun Chieh Yeh Heart Foundation of Hong Kong. The authors greatly appreciate the generous offer of pcDNA3.1/hK<INF>IR</INF>2.3 plasmid for the present study by Dr Carol A Vandenberg, University of California Santa Barbara. De-Yong Zhang and Yan-Hui Zhang are supported by post-graduate studentships from the University of Hong Kong.

References

 

DC FieldValueLanguage
dc.contributor.authorZhang, DYen_HK
dc.contributor.authorZhang, YHen_HK
dc.contributor.authorSun, HYen_HK
dc.contributor.authorLau, CPen_HK
dc.contributor.authorLi, GRen_HK
dc.date.accessioned2011-10-28T02:45:11Z-
dc.date.available2011-10-28T02:45:11Z-
dc.date.issued2011en_HK
dc.identifier.citationBritish Journal Of Pharmacology, 2011, v. 164 n. 5, p. 1469-1478en_HK
dc.identifier.issn0007-1188en_HK
dc.identifier.urihttp://hdl.handle.net/10722/142403-
dc.description.abstractBackground and Purpose The detailed molecular modulation of inward rectifier potassium channels (including the K IR2.3 channel) is not fully understood. The present study was designed to determine whether human K IR2.3 (K IR2.3) channels were regulated by protein tyrosine kinases (PTKs). Experimental Approach Whole-cell patch voltage-clamp, immunoprecipitation, Western blot analysis and site-directed mutagenesis were employed to determine the potential PTK phosphorylation of Kir2.3 current in HEK 293 cells stably expressing Kir2.3 gene. Key Results The broad-spectrum PTK inhibitor genistein (10 ÂμM) and the selective epidermal growth factor (EGF) kinase inhibitor AG556 (10 ÂμM) reversibly decreased K IR2.3 current and the effect was reversed by the protein tyrosine phosphatase inhibitor, orthovanadate (1 mM). Although EGF (100 ng·mL -1) and orthovanadate enhanced K IR2.3 current, this effect was antagonized by AG556. However, the Src-family tyrosine kinase inhibitor PP2 (10 ÂμM) did not inhibit K IR2.3 current. Tyrosine phosphorylation of K IR2.3 channels was decreased by genistein or AG556, and was increased by EGF or orthovanadate. The decrease of tyrosine phosphorylation of K IR2.3 channels by genistein or AG556 was reversed by orthovanadate or EGF. Interestingly, the response of K IR2.3 channels to EGF or AG556 was lost in the K IR2.3 Y234A mutant channel. Conclusion and Implications These results demonstrate that the EGF receptor tyrosine kinase up-regulates the K IR2.3 channel via phosphorylation of the Y234 residue of the WT protein. This effect may be involved in the endogenous regulation of cellular electrical activity. © 2011 The British Pharmacological Society.en_HK
dc.languageengen_US
dc.publisherJohn Wiley & Sons Ltd. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=0007-1188&site=1en_HK
dc.relation.ispartofBritish Journal of Pharmacologyen_HK
dc.rightsBritish Journal of Pharmacology. Copyright © John Wiley & Sons Ltd.-
dc.subjectEGFR tyrosine kinaseen_HK
dc.subjectinward rectifier K + channelsen_HK
dc.subjectprotein tyrosine kinaseen_HK
dc.subjectprotein tyrosine phosphataseen_HK
dc.subjecttyrosine phosphorylationen_HK
dc.subject.meshBlotting, Western-
dc.subject.meshElectrophysiology-
dc.subject.meshGenistein - pharmacology-
dc.subject.meshPotassium Channels, Inwardly Rectifying - genetics - metabolism-
dc.subject.meshReceptor, Epidermal Growth Factor - antagonists and inhibitors - physiology-
dc.titleEpidermal growth factor receptor tyrosine kinase regulates the human inward rectifier potassium K IR2.3 channel, stably expressed in HEK 293 cellsen_HK
dc.typeArticleen_HK
dc.identifier.emailLi, GR:grli@hkucc.hku.hken_HK
dc.identifier.authorityLi, GR=rp00476en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1111/j.1476-5381.2011.01424.xen_HK
dc.identifier.pmid21486282-
dc.identifier.pmcidPMC3221101-
dc.identifier.scopuseid_2-s2.0-80054043745en_HK
dc.identifier.hkuros197656-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-80054043745&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume164en_HK
dc.identifier.issue5en_HK
dc.identifier.spage1469en_HK
dc.identifier.epage1478en_HK
dc.identifier.isiWOS:000296472300009-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridZhang, DY=24588358100en_HK
dc.identifier.scopusauthoridZhang, YH=54381132400en_HK
dc.identifier.scopusauthoridSun, HY=53265070800en_HK
dc.identifier.scopusauthoridLau, CP=7401968501en_HK
dc.identifier.scopusauthoridLi, GR=7408462932en_HK

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