AP-1 AND NF-KAPPA-B 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 therape utic agent for bipolar affective disorder, on processes regulating gen e expression, its effects on two transcription factors, AP-1 and NF-ka ppa B, were measured in human neuroblastoma SH-SY5Y cells. The choline rgic agonist carbachol concentration-dependently stimulated AP-1 (EC50 = 2 mu M) and NF-kappa B (EC50 = 14 mu M). Pretreatment for 24 h with a therapeutically relevant concentration of lithium(1 mM) substantial ly inhibited (30-35%) carbachol-stimulation AP-1 but not NF-kappa B. I nhibition of carbachol-induced AP-1 was directly related to the concen tration of lithium (1-20 mM). Besides being differentially sensitive t o inhibition by lithium, activation of AP-1 and NF-kappa B demonstrate d different carbachol EC50 concentrations, and carbachol-induced activ ation of AP-1, but not NF-kappa B, was inhibited by treating cells wit h Ni2+, which blocks receptor-mediated calcium influx. These findings demonstrate that one mechanism by which lithium can influence the expr ession of specific genes is through the selective modulation of signal ing processes which emanate from cholinergic receptor stimulation. (C) 1997 Elsevier Science B.V.