Unexpected Down-regulation of the hIK1 Ca²⁺-activated K⁺ Channel by Its Opener 1-Ethyl-2-benzimidazolinone in HaCaT Keratinocytes
Inverse Effects on Cell Growth and Proliferation
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Date
2003-01-31
Publication Type
Journal Article
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yes
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Abstract
We used a combination of electrophysiological and cell and molecular biological techniques to study the regulation and functional role of the intermediate conductance Ca²⁺-activated K⁺ channel, hIK1, in HaCaT keratinocytes. When we incubated cells with the hIK1 opener, 1-ethyl-2-benzimidazolinone (1-EBIO), to investigate the cellular consequences of prolonged channel activity, an unexpected down-regulation of channels occurred within a few hours. The same effect was produced by the hIK1 openers chlorzoxazone and zoxazolamine and was also observed in a different cell line (C6 glioma cells). After 3 days of treatment with 1-EBIO, mRNA levels of hIK1 were substantially diminished and no channel activity was detected. Down-regulation of hIK1 was accompanied by a loss of mitogenic activity and a strong increase in cell size. After withdrawal of 1-EBIO, hIK1 mRNA and channel activity fully recovered and the cells resumed mitogenic activity. Our data present evidence for a novel feedback mechanism of hIK1 expression that appears to result from the paradoxical action of its pharmacological activator during prolonged application. Because the down-regulation of hIK1 bears immediate significance on the biological fate of keratinocytes, 1-EBIO and related compounds might emerge as potent tools to influence the proliferation of various non-excitable cells endowed with IK channels.
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published
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Journal / series
Volume
278 (5)
Pages / Article No.
3323 - 3330
Publisher
American Society for Biochemistry and Molecular Biology