AP-1 and NF-kappaB stimulated by carbachol in human neuroblastoma SH-SY5Y cells are differentially sensitive to inhibition by lithium.
In order to identify potential actions of lithium, the primary therapeutic agent for bipolar affective disorder, on processes regulating gene expression, its effects on two transcription factors, AP-1 and NF-kappaB, were measured in human neuroblastoma SH-SY5Y cells. The cholinergic agonist carbachol concentration-dependently stimulated AP-1 (EC50 = 2 microM) and NF-kappaB (EC50 = 14 microM). Pretreatment for 24 h with a therapeutically relevant concentration of lithium (1 mM) substantially inhibited (30-35%) carbachol-stimulation AP-1 but not NF-kappaB. Inhibition of carbachol-induced AP-1 was directly related to the concentration of lithium (1-20 mM). Besides being differentially sensitive to inhibition by lithium, activation of AP-1 and NF-kappaB demonstrated different carbachol EC50 concentrations, and carbachol-induced activation of AP-1, but not NF-kappaB, was inhibited by treating cells with Ni2+, which blocks receptor-mediated calcium influx. These findings demonstrate that one mechanism by which lithium can influence the expression of specific genes is through the selective modulation of signaling processes which emanate from cholinergic receptor stimulation.