It now appears that protein palmitoylation is key to this modulation. The localization of AMPA receptors is controlled by the PDZ domain protein PSD-95, which also clusters at synapses and binds to the AMPA-trafficking protein stargazin. The clustering of PSD-95 is known to require its palmitoylation. Now, Bredt and colleagues demonstrate that increased glutamate receptor activity accelerates depalmitoylation of PSD-95 and that depalmitoylation causes endocytosis and dispersion of both PSD-95 and AMPA receptors, leading to depression of synaptic strength.
“This defines a mechanism for activity-dependent changes in AMPA receptor numbers and defines protein palmitoylation as a new signaling mechanism at synapses,” says Bredt. The enzymes that add and remove PSD-95 palmitoyl groups have not been identified, but Bredt speculates that they will be Ca2+ regulated, as Ca2+ entry into the cell (e.g., through NMDA receptors) is required for AMPA dispersion. ▪