Metabolic stress opens K+ channels in hepatoma cells through a Ca2+- and protein kinase Cα-dependent mechanism

Yu Wang, Ann Sostman, Richard Roman, Sloan Stribling, Steve Vigna, Yusuf Hannun, John Raymond, J. Gregory Fitz

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

These studies of a model liver cell line evaluate the mechanisms responsible for regulated release of K+ ions during metabolic stress. Metabolic inhibition of HTC hepatoma cells by exposure to 2,4-dinitrophenol (50 μM) and 2-deoxy-D-glucose (10 mM) stimulated outward currents carried by K+ of 974 ± 75 pA at 0 mV (n = 20, p < 0.001). Currents were inhibited by chelation of intracellular Ca2+ or exposure to apamin (50 nM), an inhibitor of SK(Ca) channels. In cell-attached recordings from intact cells, removal of metabolic substrates (25/28 cells) or exposure to metabolic inhibitors (32/40 cells) opened K+selective channels with a conductance of 6.5 ± 0.2 pS. Channels had an open probability of 0.31 ± 0.08 and opened in bursts averaging 3.55 ± 0.27 ms in duration (n = 6). Metabolic stress was associated with rapid translocation of the α isoform of protein kinase C (PKCα) from cytosol to membrane; and down-regulation of PKCα by phorbol esters or exposure to the PKC inhibitor chelerythrine (10 μM) each inhibited currents. Moreover, intracellular perfusion with purified PKCα activated currents in a Ca2+- and concentration-dependent manner. These findings indicate that metabolic stress leads to opening of apamin-sensitive SK(Ca) channels in hepatoma cells through a Ca2+- and PKC-dependent mechanism and suggest that PKCα may be selectively involved in the response. This mechanism functionally couples the metabolic state of cells to membrane K+ permeability and represents a potential target for modification of liver injury associated with ischemia and preservation.

Original languageEnglish (US)
Pages (from-to)18107-18113
Number of pages7
JournalJournal of Biological Chemistry
Volume271
Issue number30
DOIs
StatePublished - 1996

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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