Lithium inhibits cell volume regulation by acting on chloride channels and modifies ultrastructures of the cell membrane in nasopharyngeal carcinoma cells

Lithium salts have been used as a class of mood stabilizing agents to treat bipolar disorders for over a century. Although lithium is known to affect cell proliferation, apoptosis and migration, the underlying mechanisms have not been well-explored. Emerging evidence indicates that cell volume regulation and volume-activated chloride channels are involved in cell proliferation, apoptosis and migration. To understand the mechanism of lithium's actions, we investigated the effect of lithium chloride on cell volume regulation and volume-activated chloride channels in the nasopharyngeal carcinoma cell line CNE-2Z. Our results show that lithium chloride attenuates regulatory volume decease induced by 47% hypotonic challenges in a concentration-dependent manner with an IC50 of 756 μM. Using the patch clamp techniques, we further show that lithium chloride concentration-dependently (IC50 = 440 μM) inhibits the volume-activated chloride current as well as the background chloride current. Furthermore, using a nanoscale atomic force microscope, we show that lithium chloride prevents the hypotonic challenge-induced changes in the ultrastructures of the cell membrane. These changes include an increase in the number and the size of the small holes, which are observed in the surface of the cell membrane under isotonic conditions. The lithium chloride-induced inhibition in cell volume regulation, in volume-activated chloride current and in the ultrastructures of the cell membrane may contribute to its effects on cell proliferation, apoptosis and migration.