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J. Biol. Chem., Vol. 277, Issue 16, 13673-13681, April 19, 2002
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From the Division of Cellular and Molecular Biology, Toronto
Western Research Institute, University Health Network and Department of
Physiology, University of Toronto, Toronto, Ontario M5T 2S8,
Canada
The human "ether-a-go-go"-related gene (HERG)
K+ channel, and its homologues are present in heart,
neuronal tissue, some cancer cells, and the MLS-9 rat microglia cell
line (Zhou, W., Cayabyab, F. S., Pennefather, P. S.,
Schlichter, L. C., and DeCoursey, T. E. (1998) J. Gen. Physiol. 111, 781-794). Despite its importance, there are
few studies of ERG modulation. In this first report of
regulation by tyrosine phosphorylation we show that MLS-9 cells express
transcripts for r-erg1 (rat homologue of HERG) and
r-erg2, and an immunoreactive doublet was identified using
an anti-HERG antibody. The constitutive tyrosine phosphorylation of the
ERG1 protein, detected by co-immunoprecipitation, was reduced by the protein-tyrosine kinase inhibitors, lavendustin A, herbimycin A,
or genistein (but not daidzein). The whole cell ERG current was reduced
by protein-tyrosine kinase inhibitors or the Src-selective inhibitory
peptide, src40-58, but not by a scrambled peptide. Conversely, the current was increased by the Src-activating peptide, srcpY, but not by an inactive analogue. Activating
endogenous Src or transfecting constitutively active v-Src altered the
voltage dependence and deactivation kinetics to produce more current at negative potentials. Co-immunoprecipitation identified an association between the channel protein and Src. Thus, r-ERG1 and Src tyrosine kinase appear to exist in a signaling complex that is well positioned to modulate this K+ channel and affect its contribution to
cellular functions.
Regulation of an ERG K+ Current by Src Tyrosine
Kinase*
and
*
This work was supported in part by Heart and Stroke
Foundation of Ontario Grant T-3726 and Canadian Institutes for Health Research (formerly MRC) Grant MT-13657 (to L. C. S.). Part of this work was published previously as abstracts (Cayabyab, F. S.,
and Schlichter, L.C. (1998) Int. J. Dev. Neurosci.
16, 561; Cayabyab, F. S., and Schlichter, L. C. (1998) Soc. Neurosci. 24, 1333).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by a Heart and Stroke Foundation of Canada Research
Traineeship. Current address: NeuroMed Technologies Inc., Don Rix
Bldg., 301-2389 Health Sciences Mall, University of British Columbia,
Vancouver, British Columbia V6T 1Z4, Canada. E-mail: fcayabyab@neuromedtech.com.
§
To whom correspondence should be addressed: MC 9-415, Toronto
Western Hospital, 399 Bathurst St., Toronto, Ontario M5T 2S8, Canada.
Tel.: 416-603-5800 (ext: 2052); Fax: 416-603-5745; E-mail: schlicht@uhnres.utoronto.ca.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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