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Article: Differential Effects of Tyrosine Kinase Inhibitors on Volume-sensitive Chloride Current in Human Atrial Myocytes: Evidence for Dual Regulation by Src and EGFR Kinases

TitleDifferential Effects of Tyrosine Kinase Inhibitors on Volume-sensitive Chloride Current in Human Atrial Myocytes: Evidence for Dual Regulation by Src and EGFR Kinases
Authors
KeywordsCell volume
EGFR kinase
Orthovanadate
Protein tyrosine phosphatase
Src family kinases
Issue Date2004
PublisherRockefeller University Press. The Journal's web site is located at www.jgp.org/
Citation
Journal Of General Physiology, 2004, v. 123 n. 4, p. 427-439 How to Cite?
AbstractTo determine whether protein tyrosine kinase (PTK) modulates volume-sensitive chloride current (I Cl.vol) in human atrial myocytes and to identify the PTKs involved, we studied the effects of broad-spectrum and selective PTK inhibitors and the protein tyrosine phosphatase (PTP) inhibitor orthovanadate (VO 4 -3). I Cl.vol evoked by hyposmotic bath solution (0.6-times isosmotic, 0.6T) was enhanced by genistein, a broad-spectrum PTK inhibitor, in a concentration-dependent manner (EC 50 = 22.4 μM); 100 μM genistein stimulated I Cl.vol by 122.4 ± 10.6%. The genistein-stimulated current was inhibited by DIDS (4,4′-diisothiocyanostilbene-2,2′-disulfonic acid, 150 μM) and tamoxifen (20 μM), blockers of I Cl.vol. Moreover, the current augmented by genistein was volume dependent; it was abolished by hyperosmotic shrinkage in 1.4T, and genistein did not activate Cl - current in 1T. In contrast to the stimulatory effects of genistein, 100 μM tyrphostin A23 (AG 18) and A25 (AG 82) inhibited I Cl.vol by 38.2 ± 4.9% and 40.9 ± 3.4%, respectively. The inactive analogs, daidzein and tyrphostin A63 (AG 43), did not alter I Cl.vol. In addition, the PTP inhibitor VO 4 -3 (1 mM) reduced I Cl.vol by 53.5 ± 4.5% (IC 50 = 249.6 μM). Pretreatment with VO 4 -3 antagonized genistein-induced augmentation and A23- or A25-induced suppression of I Cl.vol. Furthermore, the selective Src-family PTK inhibitor PP2 (5 μM) stimulated I Cl.vol, mimicking genistein, whereas the selective EGFR (ErbB-1) kinase inhibitor tyrphostin B56 (AG 556, 25 μM) reduced I Cl.vol, mimicking A23 and A25. The effects of both PP2 and B56 also were substantially antagonized by pretreatment with VO 4 -3. The results suggest that I Cl.vol is regulated in part by the balance between PTK and PTP activity. Regulation is complex, however. Src and EGFR kinases, distinct soluble and receptor-mediated PTK families, have opposing effects on I Cl.vol, and multiple target proteins are likely to be involved.
Persistent Identifierhttp://hdl.handle.net/10722/44952
ISSN
2015 Impact Factor: 4.511
2015 SCImago Journal Rankings: 3.061
PubMed Central ID
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorDu, XLen_HK
dc.contributor.authorGao, Zen_HK
dc.contributor.authorLau, CPen_HK
dc.contributor.authorChiu, SWen_HK
dc.contributor.authorTse, HFen_HK
dc.contributor.authorBaumgarten, CMen_HK
dc.contributor.authorLi, GRen_HK
dc.date.accessioned2007-10-30T06:14:17Z-
dc.date.available2007-10-30T06:14:17Z-
dc.date.issued2004en_HK
dc.identifier.citationJournal Of General Physiology, 2004, v. 123 n. 4, p. 427-439en_HK
dc.identifier.issn0022-1295en_HK
dc.identifier.urihttp://hdl.handle.net/10722/44952-
dc.description.abstractTo determine whether protein tyrosine kinase (PTK) modulates volume-sensitive chloride current (I Cl.vol) in human atrial myocytes and to identify the PTKs involved, we studied the effects of broad-spectrum and selective PTK inhibitors and the protein tyrosine phosphatase (PTP) inhibitor orthovanadate (VO 4 -3). I Cl.vol evoked by hyposmotic bath solution (0.6-times isosmotic, 0.6T) was enhanced by genistein, a broad-spectrum PTK inhibitor, in a concentration-dependent manner (EC 50 = 22.4 μM); 100 μM genistein stimulated I Cl.vol by 122.4 ± 10.6%. The genistein-stimulated current was inhibited by DIDS (4,4′-diisothiocyanostilbene-2,2′-disulfonic acid, 150 μM) and tamoxifen (20 μM), blockers of I Cl.vol. Moreover, the current augmented by genistein was volume dependent; it was abolished by hyperosmotic shrinkage in 1.4T, and genistein did not activate Cl - current in 1T. In contrast to the stimulatory effects of genistein, 100 μM tyrphostin A23 (AG 18) and A25 (AG 82) inhibited I Cl.vol by 38.2 ± 4.9% and 40.9 ± 3.4%, respectively. The inactive analogs, daidzein and tyrphostin A63 (AG 43), did not alter I Cl.vol. In addition, the PTP inhibitor VO 4 -3 (1 mM) reduced I Cl.vol by 53.5 ± 4.5% (IC 50 = 249.6 μM). Pretreatment with VO 4 -3 antagonized genistein-induced augmentation and A23- or A25-induced suppression of I Cl.vol. Furthermore, the selective Src-family PTK inhibitor PP2 (5 μM) stimulated I Cl.vol, mimicking genistein, whereas the selective EGFR (ErbB-1) kinase inhibitor tyrphostin B56 (AG 556, 25 μM) reduced I Cl.vol, mimicking A23 and A25. The effects of both PP2 and B56 also were substantially antagonized by pretreatment with VO 4 -3. The results suggest that I Cl.vol is regulated in part by the balance between PTK and PTP activity. Regulation is complex, however. Src and EGFR kinases, distinct soluble and receptor-mediated PTK families, have opposing effects on I Cl.vol, and multiple target proteins are likely to be involved.en_HK
dc.format.extent579350 bytes-
dc.format.extent19303 bytes-
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dc.format.extent2007 bytes-
dc.format.mimetypeapplication/pdf-
dc.format.mimetypetext/plain-
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dc.languageengen_HK
dc.publisherRockefeller University Press. The Journal's web site is located at www.jgp.org/en_HK
dc.relation.ispartofJournal of General Physiologyen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.rightsJournal of General Physiology. Copyright © Rockefeller University Press.en_HK
dc.subjectCell volumeen_HK
dc.subjectEGFR kinaseen_HK
dc.subjectOrthovanadateen_HK
dc.subjectProtein tyrosine phosphataseen_HK
dc.subjectSrc family kinasesen_HK
dc.subject.meshChloride Channels - metabolismen_HK
dc.subject.meshMyocytes, Cardiac - drug effects - enzymologyen_HK
dc.subject.meshProtein-Tyrosine Kinases - antagonists & inhibitorsen_HK
dc.subject.meshReceptor, Epidermal Growth Factor - metabolismen_HK
dc.subject.meshsrc-Family Kinases - metabolismen_HK
dc.titleDifferential Effects of Tyrosine Kinase Inhibitors on Volume-sensitive Chloride Current in Human Atrial Myocytes: Evidence for Dual Regulation by Src and EGFR Kinasesen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0022-1295&volume=123&issue=4&spage=427&epage=439&date=2004&atitle=Differential+effects+of+tyrosine+kinase+inhibitors+on+volume-sensitive+chloride+current+in+human+atrial+myocytes:+evidence+for+dual+regulation+by+Src+and+EGFR+kinasesen_HK
dc.identifier.emailTse, HF:hftse@hkucc.hku.hken_HK
dc.identifier.emailLi, GR:grli@hkucc.hku.hken_HK
dc.identifier.authorityTse, HF=rp00428en_HK
dc.identifier.authorityLi, GR=rp00476en_HK
dc.description.naturepublished_or_final_versionen_HK
dc.identifier.doi10.1085/jgp.200409013en_HK
dc.identifier.pmid15024039-
dc.identifier.pmcidPMC2217456-
dc.identifier.scopuseid_2-s2.0-1842786937en_HK
dc.identifier.hkuros113926-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-1842786937&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume123en_HK
dc.identifier.issue4en_HK
dc.identifier.spage427en_HK
dc.identifier.epage439en_HK
dc.identifier.isiWOS:000220795000009-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridDu, XL=9036718000en_HK
dc.identifier.scopusauthoridGao, Z=16549711200en_HK
dc.identifier.scopusauthoridLau, CP=7401968501en_HK
dc.identifier.scopusauthoridChiu, SW=12788356600en_HK
dc.identifier.scopusauthoridTse, HF=7006070805en_HK
dc.identifier.scopusauthoridBaumgarten, CM=7006283434en_HK
dc.identifier.scopusauthoridLi, GR=7408462932en_HK

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