Abstract
Membrane potential (Vmem) is a key bioelectric property of non-excitable cells that plays important roles in regulating cell proliferation. However, the regulation of Vmem itself remains largely unexplored. We found that, under nutrient starvation, during which cell division is inhibited, MKN45 gastric cancer cells were in a hyperpolarized state associated with a high intracellular chloride concentration. AMP-activated protein kinase (AMPK) activity increased, and expression of cystic fibrosis transmembrane conductance regulator (CFTR) decreased, in nutrient-starved cells. Furthermore, the increase in intracellular chloride concentration level and Vmem hyperpolarization in nutrient-starved cells was suppressed by inhibition of AMPK activity. Intracellular chloride concentrations and hyperpolarization increased after over-activation of AMPK using the specific activator AICAR or suppression of CFTR activity using specific inhibitor GlyH-101. Under these conditions, proliferation of MKN45 cells was inhibited. These results reveal that AMPK controls the dynamic change in Vmem by regulating CFTR and influencing the intracellular chloride concentration, which in turn influences cell-cycle progression. These findings offer new insights into the mechanisms underlying cell-cycle arrest regulated by AMPK and CFTR.
Highlights
Chloride channels, the most abundant anion in all organisms, are believed to contribute to Vmem, and to maintain intracellular pH and cell volume[8]
We found that elevated AMPactivated protein kinase (AMPK) activity induced hyperpolarization in MKN45 cells by inhibiting outflow of intracellular chloride and decreased the cell-surface expression of CFTR
We found that nutrient starvation induced reversible hyperpolarization and cell-cycle arrest in the gastric cancer cell line MKN45
Summary
The most abundant anion in all organisms, are believed to contribute to Vmem, and to maintain intracellular pH and cell volume[8]. The chloride current plays important roles in multiple cellular processes, including the cell cycle and proliferation[9]. CFTR is a secretory chloride channel, and acts as a conductance regulator, coordinating an ensemble of ion fluxes across the cell membrane[11,12]. In the Xenopus model, depolarization of embryonic cells by manipulating the activity of native glycine receptor chloride channel induces these drastic changes in melanocyte behavior via a serotonin-transporter-dependent increase of extracellular serotonin[28]. AMPK is involved in multiple cellular processes, including stimulation of autophagy, inhibition of cell growth and proliferation, and stress responses[40]. AMPK regulates a wide variety of ion channels, coupling ion transport processes to cellular stress and metabolic state[35,36,41]
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