Intracellular lithium and cyclic AMP levels are mutually regulated in neuronal cells

In this work, we studied the effect of intracellular 3′,5′- cyclic adenosine monophosphate (cAMP) on Li⁺ transport in SH-SY5Y cells. The cells were stimulated with forskolin, an adenylate cyclase activator, or with the cAMP analogue, dibutyryl-cAMP. It was observed that under forskolin stimulation both the Li+ influx rate constant and the Li⁺ accumulation in these cells were increased. Dibutyryl-cAMP also increased Li⁺ uptake and identical results were obtained with cortical and hippocampal neurons. The inhibitor of the Na⁺/Ca²⁺ exchanger, KB-R7943, reduced the influx of Li⁺ under resting conditions, and completely inhibited the effect of forskolin on the accumulation of the cation. Intracellular Ca²⁺ chelation, or inhibition of N-type voltage-sensitive Ca²⁺ channels, or inhibition of cAMP-dependent protein kinase (PKA) also abolished the effect of forskolin on Li⁺ uptake. The involvement of Ca²⁺ on forskolin-induced Li⁺ uptake was confirmed by intracellular free Ca²⁺ measurements using fluorescence spectroscopy. Exposure of SH-SY5Y cells to 1 mM Li⁺ for 24 h increased basal cAMP levels, but preincubation with Li⁺, at the same concentration, decreased cAMP production in response to forskolin. To summarize, these results demonstrate that intracellular cAMP levels regulate the uptake of Li⁺ in a Ca²⁺-dependent manner, and indicate that Li⁺ plays an important role in the homeostasis of this second messenger in neuronal cells.