Down-regulation of PKC alpha by lithium in vitro.

In recent years, research aimed at the elucidation of lithium's molecular mechanisms has focused on signal transduction pathways. This research has demonstrated that lithium has multiple effects on the phosphoinositide turnover signaling system. We have previously demonstrated that chronic (but not acute) in vitro exposure of HL60 cells to 1 mM lithium reduces both receptor and phorbol-ester-mediated Na+/H+ activity without affecting agonist-induced increases in intracellular Ca2+ or phosphoinositide breakdown, findings which suggest an attenuation of protein kinase C (PKC) function. The present study sought to measure the in vitro effects of lithium on PKC more directly and demonstrated that 5-day in vitro exposure of HL60 cells to either 1 mM or 10 mM lithium chloride dramatically reduces PKC alpha in both cytosolic and membrane fractions. Given the critical role of PKC in regulating neuronal signal transduction, these effects may play a major role in lithium's mood-stabilizing effects.