N-terminal palmitoylation of PSD-95 regulates association with cell membranes and interaction with K+ channel Kv1.4

Neuron. 1998 Jan;20(1):125-34. doi: 10.1016/s0896-6273(00)80440-7.


Ion channels and associated signal transduction cascades are clustered at excitatory synapses by PSD-95 and related PDZ-containing proteins. Mechanisms that target PSD-95 to synaptic membranes, however, are unknown. Here, PSD-95 is shown to partition as an integral membrane protein in brain homogenates. Metabolic labeling of brain slices or cultured cells demonstrates that PSD-95 is modified by thioester-linked palmitate, a long chain fatty acid that targets proteins to cell membranes. In fact, PSD-95 is a major palmitoylated protein in intact cells, and palmitoylated PSD-95 partitions exclusively with cell membranes. Mutagenesis indicates that palmitoylation of PSD-95 occurs on conserved N-terminal cysteines 3 and 5. Palmitoylation-deficient mutants of PSD-95 do not partition as integral membrane proteins and do not participate in PDZ-ion channel interactions in vivo. This work identifies palmitoylation as a critical regulatory mechanism for receptor interactions with PSD-95.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Brain / metabolism
  • COS Cells / metabolism
  • Cell Membrane / metabolism
  • Disks Large Homolog 4 Protein
  • Intracellular Signaling Peptides and Proteins
  • Kv1.4 Potassium Channel
  • Membrane Proteins
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Palmitic Acid / metabolism*
  • Potassium Channels / metabolism*
  • Potassium Channels, Voltage-Gated*
  • Rats


  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • Intracellular Signaling Peptides and Proteins
  • Kcna4 protein, rat
  • Kv1.4 Potassium Channel
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • postsynaptic density proteins
  • Palmitic Acid