Figure 1.

The PI3K–PKCλ–AMPAR signalling pathway. The centre of the figure depicts a GluA1/A2 heterotetrameric AMPAR, which accounts for ∼80% of hippocampal AMPARs. PI3K binds to residues 833–853 in the cytosolic C terminus of the AMPAR GluA2 subunit for localized postsynaptic signalling (Man et al, 2003). p62 binds with its atypical PKC interaction domain (AID) to the N-terminal regulatory region of PKCλ and with its Zn finger domain to the second intracellular loop of GluA1 (Jiang et al, 2009). Ca²⁺ influx via the NMDAR during high-frequency synaptic transmission can activate PIP3K via calmodulin (CaM) (Joyal et al, 1997). The consequent production of PIP3,4,5 stimulates PKCλ, which might act in part by phosphorylating S818 on GluA1. How high-frequency activity augments the p62/PKCλ–AMPAR interaction is unclear.