PICK1(protein interacting with C-kinase 1), contains an N-terminal PDZ (PSD- 95/Dlg/ZO-1) domain, a central BAR (Bin/amphiphysin/Rvs) domain and a C-terminal acidic domain. PDZ domain of PICK1 mediates its interaction with the C-termini of many membrane proteins and regulates their localization and trafficking. BAR domain of many proteins such as amphiphysin was found to bind and tubulate lipid. AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptors and ASICs (acid-activated ion channels) are two groups of ion channels interacting with PICK1. Here we report that PICK1 directly binds to lipids via its BAR domain. Lipid binding of PICK1 is required for its synaptic targeting and clustering of AMPA receptors and ASICs. PICK1 enhances synaptic targeting of AMPA receptor and...[ Read more ]

PICK1(protein interacting with C-kinase 1), contains an N-terminal PDZ (PSD- 95/Dlg/ZO-1) domain, a central BAR (Bin/amphiphysin/Rvs) domain and a C-terminal acidic domain. PDZ domain of PICK1 mediates its interaction with the C-termini of many membrane proteins and regulates their localization and trafficking. BAR domain of many proteins such as amphiphysin was found to bind and tubulate lipid. AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptors and ASICs (acid-activated ion channels) are two groups of ion channels interacting with PICK1. Here we report that PICK1 directly binds to lipids via its BAR domain. Lipid binding of PICK1 is required for its synaptic targeting and clustering of AMPA receptors and ASICs. PICK1 enhances synaptic targeting of AMPA receptor and this enhancement is depended on PICK1's lipid binding capability. There is a dynamic role for PICK1 to regulate the trafficking of its binding partners in a lipid-binding dependent way: PICK1 decreases surface expression of AMPARs but increases surface level of ASICs. In addition, PICK1 can enhance this ASIC1-mediated cell toxicity during acidosis. Taken together, our study indicates that the lipid binding of PICK1 's BAR domain is important for PICK1-regulated trafficking and function of AMPARs and ASICs.