Transport pathways for lithium ions in neuroblastoma × glioma hybrid cells at ‘therapeutic’ concentrations of Li+

Abstract The pathways of Li + transport in neuroblastoma × glioma hybrid cells were studied at 2 mM external Li + . Five components of Li + transport were identified. (1) A Na + -dependent Li + countertransport system mediating Li + transport in both directions across the plasma membrane. This transport pathway is insensitive to ouabain or external K + . It shows trans-stimulation (i.e. acceleration of Li + extrusion by external Na + and stimulation of Li + uptake by internal Na + ) and cis-inhibition (i.e. reduction of Li + uptake by external Na + ). (2) The Na + K + pump mediates Li + uptake but not Li + release in cells with physiological Na + and K + content. Li + uptake by the pump in choline media is inhibited by both external Na + and K + . In Na + media, external K + exhibits a biphasic effect: in concentrations up to about 1 mM, K + accelerates, and at higher concentrations, K + inhibits, Li + uptake by the pump. (3) Li + can enter the voltage-dependent Na + channel. Li + uptake through this pathway is stimulated by veratridine and scorpion toxin, the stimulation being blocked by tetrodotoxin. Residual pathways comprise (4) a saturable component, which is comparable to basal Na + uptake, and (5) a ouabain-resistant component promoting Li + extrusion against an electrochemical gradient in choline media. The mechanisms for Li + extrusion described here possibly explain how neuronal cells maintain the steady-state ratio of internal to external Li + below 1 during chronic exposure to 1–2 mM external Li + .