NSF ATPase and α-/β-SNAPs Disassemble the AMPA Receptor-PICK1 Complex

Luscher et al., 1999). This indicates that NSF maintains form a complex in the presence of ATP␥S. Similar a high level of synaptic AMPARs, either by preventing to SNARE complex disassembly, NSF ATPase activity their removal by endocytosis or facilitating their insertion disrupts PICK1-GluR2 interactions in this complex. ␣-by exocytosis. The same peptide treatment occludes and ␤-SNAP have differential effects on this reaction. NMDAR-dependent LTD (Luscher et al., 1999; Luthi et SNAP overexpression in hippocampal neurons leads al., 1999) and inhibition of NSF function by N-ethylmalei-to corresponding changes in AMPAR trafficking by mide (NEM) enhances AMPAR endocytosis (Luscher et acting on GluR2-PICK1 complexes. This demonstrates al., 1999). This suggests that the NSF-GluR2 interaction that the previously reported synaptic stabilization of negatively regulates LTD by inhibition of AMPAR endo-AMPARs by NSF involves disruption of GluR2-PICK1 cytosis. interactions. Furthermore, we are reporting a non-ABP/GRIP act as receptor anchors at the plasma SNARE substrate for NSF disassembly activity. membrane and at an intracellular site (Osten et al., 2000; Daw et al., 2000). The PICK1-GluR2 interaction is re-Introduction quired for the expression of some forms of LTD (Xia et al., 2001; Kim et al., 2001), suggesting that PICK1 Recent studies reveal that AMPA receptor (AMPAR) traf-stimulates AMPAR removal from the synaptic plasma ficking is involved in synaptic plasticity (Luscher et al., membrane by endocytosis. In support of this, NMDAR-2000; Man et al., 2000; Carroll et al., 2001). Long-term dependent AMPAR internalization in hippocampal neu-potentiation (LTP) in hippocampus involves insertion of rons involves GluR2-PICK1 interactions (Iwakura et al., AMPARs into the synaptic membrane by exocytosis (Shi 2001), and we have demonstrated that PICK1 overex-et al., 1999; Lu et al., 2001). Some forms of long-term pression results in translocation of GluR2 homomers to depression (LTD) in the cerebellum (Matsuda et al., 2000; an intracellular compartment (Perez et al., 2001). Wang and Linden, 2000) and hippocampus (Luscher et NSF and PICK1 are two proteins thought to have cru-al., 1999; Beattie et al., 2000; Iwakura et al., 2001) are cial but independent roles in AMPAR trafficking. These mediated at least in part by AMPAR endocytosis. studies, plus the established role of NSF as a disassem-Proteins have been identified that bind the C terminus bling chaperone, suggest that NSF might regulate of GluR2 subunit, and are involved in AMPAR trafficking GluR2-PICK1 interactions. Here, we show that this is (Braithwaite et al., 2000; Scannevin and Huganir, 2000). indeed the case. …