Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 275, Issue 34, Pages 26050-26057Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M001576200
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- NCI NIH HHS [P30 CA13330] Funding Source: Medline
- NIDDK NIH HHS [R01 DK46952, P33 DK41296] Funding Source: Medline
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To determine whether K-ATP channels control liver growth, we used primary rat hepatocytes and several human cancer cell lines for assays. K-ATP channel openers (minoxidil, cromakalim, and pinacidil) increased cellular DNA synthesis, whereas K-ATP channel blockers (quinidine and glibenclamide) attenuated DNA synthesis. The channel inhibitor glibenclamide decreased the clonogenicity of HepG2 cells without inducing cytotoxicity or apoptosis. To demonstrate the specificity of drugs for K+ channels, whole-cell patch-clamp recordings were made. Hepatocytes revealed K+ currents with K-ATP channel properties. These K+ currents were augmented by minoxidil and pinacidil and attenuated by glibenclamide as well as tetraethylammonium, in agreement with established responses of K+, channels. Reverse transcription of total cellular RNA followed by polymerase chain reaction showed expression of K-ATP channel-specific subunits in rat hepatocytes and human liver cell lines. Calcium fluxes were unperturbed in glibenclamide-treated HepG(2) cells and primary rat hepatocytes following induction with ATP and hepatocyte growth factor, respectively, suggesting that the effect of K-ATP channel activity upon hepatocyte proliferation was not simply due to indirect modulation of intracellular calcium. The regulation of mitogen-related hepatocyte proliferation by K-ATP channels advances our insights into liver growth control. The findings have implications in mechanisms concerning liver development, regeneration, and oncogenesis.
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