Voltage-dependent delayed rectifier K + (Kv) channels are fundamental components in the regulation of neuronal excitability. We found that nerve growth factor (NGF) treatment of PC12 cells induced a hyperpolarizing shift of the Kv current activation curve by about 15 mV. This effect was similar to the effect of the modulatory subunit, Kvβ, on the cloned Kv channel, and required the activity of protein kinase C (PKC)ζ. Since NGF treatment of PC12 cells is known to increase the expression of p62 protein, which binds both to Kvβ and to PKCζ, our results are consistent with the model in which p62 functions as a physical link in the assembly of signaling complex, PKCζ-p62-Kv channel. In agreement with this model, the transient expression of p62 induced the same change in the Kv current activation curve as NGF, and the suppression of p62 expression inhibited the effect of NGF. The amount of bound Kvβ to p62 was increased by NGF treatment. These results suggest that the increased p62 protein induces the formation of the signaling complexes, enabling PKCζ to modulate Kv channels. Thus, this may constitute a new way of modulating Kv channel activities.