Role of Palmitoylation of Postsynaptic Proteins in Promoting Synaptic Plasticity

Abstract

Many postsynaptic proteins undergo palmitoylation, the reversible attachment of the fatty acid palmitate to cysteine residues, which influences trafficking, localization, and protein interaction dynamics. Both palmitoylation by palmitoyl acyl transferases (PAT) and depalmitoylation by palmitoyl-protein thioesterases (PPT) is regulated in an activity-dependent, localized fashion. Recently, palmitoylation has received attention for its pivotal contribution to various forms of synaptic plasticity, the dynamic modulation of synaptic strength in response to neuronal activity. For instance, palmitoylation and depalmitoylation of the central postsynaptic scaffold protein postsynaptic density-95 (PSD-95) is important for synaptic plasticity. Here, we provide a comprehensive review of studies linking palmitoylation of postsynaptic proteins to synaptic plasticity.

Keywords: AMPAR; LTD; LTP; NMDAR; PSD-95; homeostatic plasticity.

Figure 1

Protein Palmitoylation. (A) The thioester bond of palmitic acid (palm), which is covalently linked to coenzyme A (CoA), is transferred to cysteine by specialized palmitoyl acyl-transferases (PAT). Selective palmityol protein-thioesterases (PPT) catalyze hydrolytic cleavage of palmitic acid from cysteine moieties. (B) Membrane topology of ZDHHC proteins. ZDHHCs form four (left) or six (right) transmembrane domains (TMDs) with N- and C-termini in the cytoplasm. The conserved DHHC domain is indicated in red, ankyrin repeats are indicated in blue. The consensus sequence of the DHHC domain is given at the bottom (Nadolski and Linder, 2007).

Figure 2

Palmitoylation of AMPA-type glutamate receptors (AMPAR) and NMDA-type glutamate receptors (NMDAR). (A) Topology of AMPAR subunits. (B) Sequence alignment of the GluA1–4 regions that harbor palmitoylation sites. (C) Topology of NMDAR subunits. (D) Sequence alignment of the GluN2A and GluN2B regions that harbor palmitoylation sites. Palmitoylation sites are indicated by red and blue stars and arrows in (A,C). Orange shading in (B,D) indicates TMD, red and blue shading cysteines corresponding to red and blue stars in (A,C).

Figure 3

Palmitoylation of A-kinase anchoring protein 5 (AKAP5). Shown are AKAP5 palmitoylation sites (orange shading) within the N-terminal polybasic regions A and C in relation to known binding sites for AKAP5 associated proteins (reviewed in Sanderson and Dell’Acqua, ; Woolfrey and Dell’Acqua, ; Patriarchi et al., 2018). Residue numbering refers to human AKAP5. The β₂-adrenoreptor (β₂AR), cadherin, F-actin, and the voltage-activated potassium channel K_V7.2 interact with the N-terminal half of AKAP5. All three polybasic regions bind to Ca²⁺/Calmodulin (Ca²⁺/CaM) and phosphatidylinositol 4,5-bisphosphate (PIP₂). Adenylyl cyclases 5 and 6 (AC5/6) bind polybasic region B and PKC binds to polybasic region A. postsynaptic density-95 (PSD-95) and SAP97 interact through their Src homology 3 (SH3) and GK domains with the center of AKAP5, which also binds the K⁺ channel K_V4.2. PP2B interacts near the center of AKAP5 and protein kinase A (PKA) with a motif about 20 residues upstream of the C-terminus, while the α₁1.2 subunit of Ca_V1.2 binds to the last ~15 residues at the C-terminus.

Figure 4

N-terminal splice variants of PSD-95, PSD-93, SAP97, and SAP102. (A) Depicted are segments classified by sequence homology with their number of residues. Palmitoylation sites are indicated by red stars. For instance PSD-95 and SAP97 exist in two N-terminal splice variants, an α isoform, which is palmitoylated within its first 10 residues (Cys3 and Cys5), and a β variant containing an L27 interaction motif encoded on alternatively spliced exons (Chetkovich et al., ; Schlüter et al., 2006). PSD-93 has six N-terminal splice variants, two of which are palmitoylated: PSD-93α, which is most similar to PSD-95α, and PSD93β (Parker et al., ; Krüger et al., 2013). The N-terminus of SAP102 only exists in one splice variant which contains a L27 domain and is not palmitoylated (Müller et al., 1996). (B) Sequence alignment of the N-termini of PSD-95α, SAP97α, PSD-93α, and PSD-93β. Red shading indicates palmitoylated cysteines corresponding to red stars in (A).

Figure 5

Model of postsynaptic PSD-95 anchoring and its displacement upon Ca²⁺ influx. Under basal conditions (left), PSD-95 is kept at postsynaptic sites by palmitoylation (PAT protein ZDHHC8) and binding to α-actinin. Ca²⁺ influx likely stimulates PSD-95 depalmitoylation (PPT), which allows binding of Ca²⁺/CaM to shift the equilibrium of palmitoylated, α-actinin—bound PSD-95 to non-palmitoylated PSD-95 in part by Ca²⁺/CaM capping of the N-terminus of PSD-95, thereby preventing re-palmitoylation. Ca²⁺/CaM also competes with and thereby displaces α-actinin from the N-terminus of PSD-95 when it is depalmitoylated.