Lithium carbonate could be used to treat or prevent brain damage following traumatic injury and neurodegenerative diseases. It has been shown that its protective effect is related to protein kinase C (PKC) and extracellular signal-related kinase (ERK). It was demonstrated that PDBu, a PKC activator, inhibited amplitudes of delayed rectifier potassium current (I_K) and produced a hyperpolarizing shift in the activation-voltage curve. The responses to PDBu were inhibited by lithium carbonate (50 μmol/L). Further studies showed that when pretreated with MEK/ERK inhibitor U0126 (20 μmol/L), although PDBu significantly reduced I_K, lithium did not reverse the effect of PDBu. Thus, the results suggested that PKC signaling cascades, along with MAPK (mitogen-activated protein kinase) pathway, were required in the phosphorylation of potassium channel, which was presented by regulation of potassium channel characteristic. AC-cAMP and their cross-talk with GC-cGMP pathway could also modulate the effect of lithium on PKC activation, which could be one of underlying mechanisms likely related to neuroprotective effect of lithium.