Figure 10.

Model for the function of PICK1 in NMDAR-dependent LTD. In the basal state, PICK1 exists in a closed conformation (0) that requires electrostatic interactions involving the N-terminal acidic motif and perhaps the PDZ domain. During the induction of LTD, calcium influx through activated NMDARs promotes endocytosis of AMPARs in a PICK1-independent fashion (1, 2) while also relieving inhibitory intramolecular interaction in PICK1 (3). Calcium binding to PICK1 promotes an open configuration that exposes the BAR domain and perhaps other portions of the protein, which mediate the recruitment of PICK1 to endosomes (4). The association of PICK1 with recently endocytosed AMPARs delays or prevents their recycling to the postsynaptic membrane (5).