Figure 3

Three hypotheses regarding the role of aPKCs in pain plasticity taking into account recent findings on PKMζ knockout mice: A ₁ and A ₂ ) One possibility is that while cortical and hippocampal late-LTP is dependent on aPKC function through trafficking of AMPA receptors (AMPAR) this mechanism is not shared in the dorsal horn. In the dorsal horn PKMζ might be necessary and sufficient for certain forms of pain plasticity but this is not functionally linked to LTP or AMPAR trafficking and therefore involves a novel, undiscovered mechanism. Another possibility (B) is that at all CNS synapses aPKCs can serve a functionally redundant role and the absence of PKMζ fails to lead to a strong phenotype because PKCλ, which is also ZIP-sensitive, can functionally replace PKMζ in its absence. C) A final possibility is that ZIP targets a totally distinct mechanism to induce neuronal plasticity, however, such a mechanism is likely stimulated by NGF/p75-, BDNF/trkB- and mGluR1/5-dependent mechanisms that may also, in some cases, be linked to AMPAR trafficking as an endpoint signaling output of the ZIP-sensitive target.