AMPA receptors and their minions: auxiliary proteins in AMPA receptor trafficking

Abstract

To correctly transfer information, neuronal networks need to continuously adjust their synaptic strength to extrinsic stimuli. This ability, termed synaptic plasticity, is at the heart of their function and is, thus, tightly regulated. In glutamatergic neurons, synaptic strength is controlled by the number and function of AMPA receptors at the postsynapse, which mediate most of the fast excitatory transmission in the central nervous system. Their trafficking to, at, and from the synapse, is, therefore, a key mechanism underlying synaptic plasticity. Intensive research over the last 20 years has revealed the increasing importance of interacting proteins, which accompany AMPA receptors throughout their lifetime and help to refine the temporal and spatial modulation of their trafficking and function. In this review, we discuss the current knowledge about the roles of key partners in regulating AMPA receptor trafficking and focus especially on the movement between the intracellular, extrasynaptic, and synaptic pools. We examine their involvement not only in basal synaptic function, but also in Hebbian and homeostatic plasticity. Included in our review are well-established AMPA receptor interactants such as GRIP1 and PICK1, the classical auxiliary subunits TARP and CNIH, and the newest additions to AMPA receptor native complexes.

Keywords: AMPA receptors; CNIH; GRIP1; MAGUK; PICK1; Synapse; TARP; Trafficking.

Fig. 1

Regulation of AMPAR trafficking by GRIP1 and PICK1. The PDZ domain-containing GRIP1 and PICK1 regulate surface AMPAR in opposite directions: GRIP1 primarily promotes AMPAR surface insertion, stabilization, and reinsertion after internalization, while PICK1 acts on internalization and intracellular anchorage. Their interaction with GluA2 subunits is regulated by GluA2 phosphorylation on the serine 880, which favors GluA2–PICK1 binding over GluA2–GRIP1. GRIP1 interaction with ephrinB ligands stabilizes surface AMPARs, at spine (ephrinB2, via the phosphorylation of ephrinB2 serine-9) or shaft (ephrinB3) synapses. Following internalization, PICK1–GluA2 also inhibits actin polymerization. PICK1 regulates AMPAR sorting, while GRIP1 also transports AMPARs to the synapse by interacting with the motor proteins KIF1A and KIF5; cargo release from KIF5 and the microtubules requires phosphorylation of GRIP1–Thr956 residue. Conversely, GRIP1 interaction with MAP1B-LC leads to AMPAR–GRIP1 trapping on the microtubules. EE early endosome, RE recycling endosome. Note for all figures: posttranslational modifications (with the causative enzymes, when known) and direct partners of AMPAR interactants relevant for their regulation of AMPAR trafficking are also included. No stoichiometry is implicated; binding sites are indicative only, and size ratios are not to scale

Fig. 2

Regulation of AMPAR trafficking by PSD95 and TARP γ2/stargazin. PSD95 and TARP γ2/stargazin regulate AMPAR synaptic trapping. PSD95 anchors stargazin-bound freely diffusing AMPARs at the PSD, thereby enhancing synaptic strength. Stargazin phosphorylation in its cytoplasmic tail promotes PSD95 binding; upon dephosphorylation, stargazin-bound AMPARs are endocytosed or diffuse out of the synapse. Additional posttranslational modifications on PSD95 or stargazin modulate this binding in either direction. Stargazin also regulates AMPAR synaptic trafficking by interacting with MAP1A-LC2

Fig. 3

Regulation of GluA1 trafficking by SAP97. SAP97 specifically regulates GluA1-containing AMPARs in an isoform-specific manner. βSAP97 directs GluA1 to the extrasynaptic pool, while αSAP97 preferentially targets GluA1 to synapses

Fig. 4

Regulation of AMPAR trafficking by TARP γ3, γ4, γ7, and γ8, CNIH and GSG1L. TARP γ3, γ4, γ7, and γ8, CNIH2 and 3, and GSG1L modulate AMPAR trafficking to and at the synapse. γ3, γ4, and γ8 and CNIH2 together, target AMPARs to the extrasynaptic pool. γ8 and CNIH2 also cooperatively regulate AMPAR lateral diffusion to and anchoring at the synapse, by binding MAGUK proteins. TARP γ7 and CNIH3 are also present at the synapse. GSG1L, on the other hand, promotes AMPAR endocytosis and negatively regulates AMPAR trafficking to the synapse

Fig. 5

Regulation of AMPAR trafficking by Shisa proteins. Shisa6 and Shisa9 favor AMPAR stabilization at the synapse by binding to PSD95. Shisa9 is present in γ8-bound AMPAR complexes and binds several other PDZ domain-containing synaptic proteins; it also forms a complex with PICK1 and PKC upon trafficking to the synapse

Fig. 6

Newcomers in AMPAR complexes. Newly described constituents of synaptic AMPAR complexes include PRRT1, which targets AMPARs to the extrasynaptic pool; LRRTM proteins, which maintain the pool of surface AMPARs; ABHD6, which negatively regulates surface AMPARs and stargazin; Noelin-1, which negatively regulates lateral mobility of AMPARs (extrasynaptic GluA1- and GluA2-containing receptors; synaptic GluA1-containing receptors); and Rap2b, which has been shown to trigger AMPAR endocytosis indirectly, by recruiting effectors. A postsynaptic role of other interactants, such as neuritin, brorin, brorin-like or PRRT2, is still unknown

Fig. 7

Endosomal constituents of AMPAR complexes. ER-specific AMPAR complexes ensure their proper biogenesis and prime them for synaptic partners, such as TARP and CNIH. These ER-specific interactants include CPT-1c and FRRS1L, which bind together, providing a platform for GluA subunits and subsequently Sac1, PORCN, and ABHD6/12 binding. Several TARPs, CNIH2, PICK1, and Noelin-1 have also been involved in regulating AMPAR early trafficking