Protein kinase C (PKC) is a key enzyme involved in various types of signal transduction, and it is most abundant in the nervous system. Available evidence suggests that PKC plays a prominent role in neuronal transmission. PKC is a member of a family consisting of at least eleven subspecies: α, βI, βII, γ, δ, ε, η, θ, μ, ζ and λ. The individual role of each subspecies could not be demonstrated because of the homologous structure of the PKC subspecies. We studied the distinct functional roles of PKC subspecies in the central nervous system by defining the detailed localization of each subspecies. The immunocytochemical localization suggested that cPKCs (α, βI, βII, and γ) function postsynaptically, while ε-PKC preferentially modulates the synaptic efficacy in the presynapse. GAP-43, a presynaptic PKC substrate involved in neuronal plasticity, was preferentially phosphorylated by ε-PKC rather than α, β and γ -PKC. As the ε-PKC could be activated by arachidonic acid, it is strongly suggested that in the case of LTP, the presynaptic ε-PKC is activated by arachidonic acid released postsynaptically and phosphorylates GAP-43, resulting in the increase in glutamate release.