Model for compartmentalized synaptic palmitoylation of PSD-95 by mobile DHHC2. (A) Certain palmitoylated proteins such as the Gα subunit shuttle between the plasma membrane and the Golgi in nonpolarized cells. Golgi-resident DHHC3 and a putative PPT at the plasma membrane can mediate this constitutive shuttling. In neurons, DHHC3 localizes at the Golgi apparatus and mediates constitutive palmitoylation of various substrates, including Gα and PSD-95. (B and C) PSD-95 shuttling in dendrites. (B) A dynamic equilibrium exists between palmitoylated postsynaptic PSD-95 and nonpalmitoylated cytosolic PSD-95. Depalmitoylated PSD-95 diffuses into the spine and dendritic shaft. DHHC2 PAT mainly localizes in dendritic shafts on vesicles and mediates dendritic PSD-95 palmitoylation. PSD, postsynaptic density. (C) When synaptic activity is blocked, DHHC2 vesicles move into spines. This translocated DHHC2 palmitoylates spinous PSD-95; the increased postsynaptic PSD-95 thereby contributes to AMPAR homeostasis.