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Palmitoylation-mediated synaptic regulation of AMPA receptor trafficking and function - PubMed

Review

Palmitoylation-mediated synaptic regulation of AMPA receptor trafficking and function

Heesung Sohn et al. Arch Pharm Res. 2019 May.

Abstract

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is a major glutamate-gated ion channel in the brain and is important for synaptic transmission, synaptic plasticity, and learning. Palmitoylation, a post-translational modification, is a critical process regulating AMPAR trafficking, synaptic function and plasticity, and learning and memory in health and diseases. In this review, we discuss current knowledge on the palmitoylation-dependent regulation of AMPAR trafficking and functions. We focus on the palmitoylation of AMPARs and other synaptic proteins that directly or indirectly interact with AMPARs, including postsynaptic density 95, glutamate receptor-interacting protein/AMPAR-binding protein, A-kinase anchoring protein 79/150, and protein interacting with C kinase 1. Finally, we discuss what future studies should address in the field of palmitoylation-dependent AMPAR trafficking and function with regard to physiology and neurodegenerative diseases.

Keywords: AMPAR trafficking; Neurodegenerative disease; Palmitoylation; Synapse; Synaptic plasticity; Synaptic proteins.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) structure and palmitoylation. Schematic diagrams show each of the four AMPAR subunits. In each diagram, the large extracellular N-terminal domain includes S1, which forms the glutamate binding site together with S2 that is located on the extracellular loop linking transmembrane domain 3 (TMD3) and TMD4. Four hydrophobic TMDs including three membrane-spanning TMDs (TMD1, TMD3, and TMD4) and one membrane-embedded TMD (TMD2) and three intracellular domains (intracellular loop1, loop2, and the cytoplasmic tail) are shown. Palmitoylation sites for each subunit are marked in red

Fig. 2
Fig. 2

Interaction network between palmitoyl acyltransferases (PATs)/depalmitoylating enzymes and their synaptic substrates. Only the PAT/depalmitoylating enzyme–substrate pairs described in this review are shown. Blue circles, PAT enzymes; red circles, depalmitoylating enzymes; black circles, synaptic substrates. PSD-95, postsynaptic density 95; GRIP1, glutamate receptor-interacting protein; AKAP79/150, A-kinase anchoring protein 79/150; PICK1, protein interacting with C kinase 1; ABHD17, α/β-hydrolase domain-containing protein 17

Fig. 3
Fig. 3

AMPAR palmitoylation and regulation of AMPARs by palmitoylation of synaptic proteins. Palmitoylation at Cys811 in the GluA1 C-terminus inhibits the interaction of GluA1 with 4.1N and triggers activity-dependent endocytosis of AMPARs. PSD-95 palmitoylations at Cys3 and Cys5 mediated by DHHC2, DHHC3, DHHC5, DHHC7, DHHC8, and DHHC15, stabilize PSD-95-AMPAR interaction via Stargazin. GRIP1b palmitoylation targets GRIP1b to recycling endosomes and enhances activity-dependent recycling of GluA2-containing AMPARs to the plasma membrane. AKAP79 palmitoylations at Cys36 and Cys129 mediated by DHHC2 are necessary for AKAP79 targeting to recycling endosomes and dendritic spines. PSD-95, postsynaptic density 95; GRIP1, glutamate receptor-interacting protein; AKAP79/150, A-kinase anchoring protein 79/150

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References

    1. Anggono V, Clem RL, Huganir RL. PICK1 loss of function occludes homeostatic synaptic scaling. J Neurosci. 2011;31:2188–2196. doi: 10.1523/JNEUROSCI.5633-10.2011. - DOI - PMC - PubMed
    1. Anggono V, Koc-Schmitz Y, Widagdo J, Kormann J, Quan A, Chen CM, Robinson PJ, Choi SY, Linden DJ, Plomann M, Huganir RL. PICK1 interacts with PACSIN to regulate AMPA receptor internalization and cerebellar long-term depression. Proc Natl Acad Sci USA. 2013;110:13976–13981. doi: 10.1073/pnas.1312467110. - DOI - PMC - PubMed
    1. Banke TG, Bowie D, Lee H, Huganir RL, Schousboe A, Traynelis SF. Control of GluR1 AMPA receptor function by cAMP-dependent protein kinase. J Neurosci. 2000;20:89–102. doi: 10.1523/JNEUROSCI.20-01-00089.2000. - DOI - PMC - PubMed
    1. Bhattacharyya R, Barren C, Kovacs DM. Palmitoylation of amyloid precursor protein regulates amyloidogenic processing in lipid rafts. J Neurosci. 2013;33:11169–11183. doi: 10.1523/JNEUROSCI.4704-12.2013. - DOI - PMC - PubMed
    1. Borgdorff AJ, Choquet D. Regulation of AMPA receptor lateral movements. Nature. 2002;417:649–653. doi: 10.1038/nature00780. - DOI - PubMed

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