Palmitoylation-dependent regulation of glutamate receptors and their PDZ domain-containing partners

Abstract

In recent years, it has become clear that both AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid)- and NMDA (N-methyl-D-aspartate)-type glutamate receptors, and many of their interacting partners, are palmitoylated proteins. Interfering with palmitoylation dramatically affects receptor trafficking and distribution and, in turn, can profoundly alter synaptic transmission. Increased knowledge of synaptic palmitoylation not only will aid our understanding of physiological neuronal regulation, but also may provide insights into, and even novel treatments for, neuropathological conditions. In the present paper, we review recent advances regarding the regulation of ionotropic glutamate receptor trafficking and function by palmitoylation.

Figure 1. Two distinct roles for palmitoylation in trafficking and targeting of AMPA- and NMDA-type glutamate receptors

(A) In neurons transfected with DHHC3 (orange), both AMPARs (red) and NMDARs (blue) are palmitoylated, causing their retention in the Golgi. Only depalmitoylated receptors can traffic forward to the plasma membrane. AMPAR retention requires a site near the AMPAR channel pore, whereas NMDAR retention requires a cluster of cysteine residues (cysteine cluster II) in the NR2 C-terminus. (B) Additional sites on both AMPARs and NMDARs are also palmitoylated. These sites do not affect initial targeting to the plasma membrane. However, a C-terminal juxtamembrane site regulates activity-induced internalization of AMPARs, whereas a distinct cluster of cysteines residues (cysteine cluster I) regulates constitutive internalization of NMDARs.

Figure 2. Possible mechanism for the selective loss of synaptic AMPARs and PSD-95 caused by 2-Br

Under basal conditions, PSD-95 is palmitoylated at synapses and probably forms distinct complexes with both NMDARs and AMPARs. NMDARs bind PSD-95 directly, whereas AMPARs bind PSD-95 via TARPs. Acute (6–8 h) 2-Br treatment depalmitoylates and declusters PSD-95. This leads to diffusion of synaptic AMPARs to extra-synaptic and/or internal sites. However, despite the loss of synaptic PSD-95, synaptic NMDARs are minimally affected, perhaps because they are stabilized by other protein–protein interactions.

Figure 3. Unique substrate recognition by DHHC5/DHHC8 PATs allows palmitoylated GRIP1b to regulate vesicular AMPAR trafficking

(A) The C-terminal PDZ ligands of DHHC5 and DHHC8 bind GRIP1b. This binding is necessary for the recognition of GRIP1b as a substrate for palmitoylation. (B) Palmitoylated GRIP1b is targeted to recycling endosomes, where it accelerates activity-dependent recycling of GluA2-containing AMPARs back to the plasma membrane.