Fig. 9. Model for a role of cPLA₂ in LTD induction. AMPA and PMA can mimic the stimuli that induce the depression of synaptic transmission in Purkinje cells. LTD of synaptic activity is primarily expressed by the reduction in the number of postsynaptic AMPA receptors containing the GluR2 subunit. Phosphorylation of GluR2 at Ser880 by PKC reduces its stabilizing interaction with GRIP and causes GluR2 to preferentially bind PICK1, leading to its subsequent internalization to early endosomes. Stimulation of AMPA receptors promotes a large Ca²⁺ influx through voltage-gated P-type Ca²⁺ channels, which in turn triggers cPLA₂ translocation to the dendritic and somatic Golgi membranes. Simultaneous phosphorylation of cPLA₂ at Ser505 by ERK leads to an increase in its enzymatic activity. Following the coincidence detection of the large Ca²⁺ signaling and activation of the PKC-MEK-ERK signaling pathway, cPLA₂ is activated to produce free arachidonic acid. This switches AMPA receptors from the recycling pathway to the degradative pathway by regulating endosome trafficking or lysosomal activity and ensures the persistent decrease in surface expression of AMPA receptors. Regulatory molecules that provide a direct link between arachidonic acid and the sorting of internalized AMPA receptors remain to be identified. AA, arachidonic acid; DAG, diacylglycerol; IP₃, Ins(1,4,5)P₃.