K(ATP) channels regulate mitogenically induced proliferation in primary rat hepatocytes and human liver cell lines: Implications for liver growth control and potential therapeutic targeting

Harmeet Malhi, Adil N. Irani, Pankaj Rajvanshi, Sylvia O. Suadicani, David C. Spray, Thomas V. McDonald, Sanjeev Gupta

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Abstract

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(ATP) 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 HepG2 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.

Original languageEnglish (US)
Pages (from-to)26050-26057
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number34
DOIs
StatePublished - Aug 25 2000

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Liver
Rats
Hepatocytes
Adenosine Triphosphate
Cells
Cell Line
Growth
Glyburide
Pinacidil
Minoxidil
Therapeutics
Hep G2 Cells
Cromakalim
Calcium
Liver Regeneration
Tetraethylammonium
Quinidine
Hepatocyte Growth Factor
Polymerase chain reaction
DNA

ASJC Scopus subject areas

  • Biochemistry

Cite this

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abstract = "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(ATP) 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 HepG2 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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T1 - K(ATP) channels regulate mitogenically induced proliferation in primary rat hepatocytes and human liver cell lines

T2 - Implications for liver growth control and potential therapeutic targeting

AU - Malhi, Harmeet

AU - Irani, Adil N.

AU - Rajvanshi, Pankaj

AU - Suadicani, Sylvia O.

AU - Spray, David C.

AU - McDonald, Thomas V.

AU - Gupta, Sanjeev

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