Auxiliary subunits of the AMPA receptor: The Shisa family of proteins

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Abstract

AMPA receptors mediate fast synaptic transmission in the CNS and can assemble with several types of auxiliary proteins in a spatio-temporal manner, from newly synthesized AMPA receptor tetramers to mature AMPA receptors in the cell membrane. As such, the interaction of auxiliary subunits with the AMPA receptor plays a major role in the regulation of AMPA receptor biogenesis, trafficking, and biophysical properties. Throughout the years, various ‘families’ of proteins have been identified and today the approximate full complement of AMPAR auxiliary proteins is known. This review presents the current knowledge on the most prominent AMPA-receptor-interacting auxiliary proteins, highlights recent results regarding the Shisa protein family, and provides a discussion on future research that might contribute to the discovery of novel pharmacological targets of auxiliary subunits.

Introduction

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are ionotropic glutamate receptors expressed at the neuronal postsynaptic membrane and mediate fast synaptic transmission in the CNS [1]. AMPAR subunit composition, phosphorylation state, and changes in the number are well known to directly affect synaptic transmission and plasticity [2]. In addition, AMPARs have been found to associate with a wide range of auxiliary proteins, which play a critical role in regulating intracellular trafficking, expression at the synaptic membrane, and AMPAR functional properties [3]. Differential expression of AMPAR core subunits and their co-assembly with auxiliary proteins dramatically increases receptor diversity and modulatory potential in the CNS [4,5]. The first family of AMPAR auxiliary subunits identified were the transmembrane AMPAR regulatory proteins (TARPs), of which TARP γ2 (stargazin) was found to be absent in the severely ataxic stargazer mouse mutant [6,7]. Since then, the advent of interaction proteomics has enabled the identification of a full complement of AMPAR associated proteins [8,9].

In 2010, interaction proteomics led to the identification of Shisa9/CKAMP44 as a novel AMPAR-interacting protein [10], whose structure and function were distinct from other established auxiliary subunits [11,12]. More specifically, Shisa9 was characterized as a single-pass transmembrane protein that induced fast and strong desensitization of AMPAR currents within the hippocampus. In the past few years, several additional members of the Shisa family have been reported to exert a role as AMPAR modulatory proteins, namely Shisa6/CKAMP52 [13, 14, 15∗∗], Shisa7/CKAMP59 [13,16], and Shisa8/CKAMP39 [13]. Although the Shisa family members share a high structural similarity, they are very distinct in both their (brain) regional expression profile and their modulation of AMPAR function [13,17]. This review provides a short overview of the known AMPAR auxiliary subunits including their function and effect on AMPARs while highlighting the Shisa protein family.

Section snippets

Auxiliary subunits

AMPARs assemble with a wide range of auxiliary subunits during their life cycle [3,5,18], from the moment of synthesis in the endoplasmic reticulum (ER) to full integration at postsynaptic sites [5]. Multiple studies using electrophysiology, proteomics, imaging, and mutagenesis have elucidated the many important functions of these proteins [5,18]. Apart from AMPAR assembly, trafficking, and expression at the synapse, auxiliary subunits are directly involved in the regulation of the receptor's

Shisa9

The type-I transmembrane protein Shisa9 (CKAMP44) was discovered by interaction proteomics in 2010 and described as the first Shisa family member interacting with AMPARs [10]. Shisa9 specifically associates with AMPARs independent of subunit-type [10]. The 44 kDa protein Shisa9 is widely expressed throughout the brain and is most abundant in the dentate gyrus (DG) of the hippocampus [10]. Recent large-scale single-cell RNA sequencing studies of the hippocampus CA1 revealed the highest

Shisa6

Shisa6 (CKAMP52) was recently identified as an additional constituent of native AMPAR complexes and is closely related to the AMPAR auxiliary protein Shisa9 [8,10,14]. Shisa6 shares the majority of its structural features with Shisa9, as both are type-I single-pass transmembrane proteins that contain an extracellular cysteine-rich domain, a proline-rich intracellular region, and a C-terminal type II PDZ-ligand motif [14,64]. Shisa6 is highly expressed in the cerebellum and all hippocampal

Shisa7

Shisa7 (CKAMP59), recently identified as an AMPAR-interacting protein [13,16], shares all major structural characteristics present in Shisa6 and Shisa9, including the N-terminal Cysteine-rich region and the C-terminal PDZ type II binding motif [16]. Shisa7 is highly expressed in the hippocampus, striatum, amygdala, cortex, and olfactory bulb [13,16]. In situ hybridization analyses from the Allen Brain Atlas shows high expression of Shisa7 in both CA regions and the DG of the hippocampus,

Shisa8

The least studied AMPAR-interacting member of the Shisa protein family is Shisa8 (CKAMP39). The highest expression of Shisa8 was observed in the cerebellum and olfactory bulb, with almost no expression in other brain regions [13]. In the study of Farrow et al., co-expression of Shisa8 and AMPAR subunits GluA1 and GuA2 in Xenopus oocytes showed that it co-immunoprecipitated with both subunits, and modulated AMPAR gating properties [13]. In HEK293 cells, Shisa8 significantly affected

Perspective: pharmacological targeting of interfaces between AMPARs and auxiliary proteins

Auxiliary proteins interacting with the AMPAR play a critical role in the CNS by modulating receptor synthesis, trafficking, surface expression, and gating properties. With current knowledge, a broad range of AMPAR auxiliary proteins seems to modulate the receptor's function at different cellular locations, from the newly synthesized tetramers at the early stage of biogenesis to mature AMPARs in the cell membrane. Throughout the years, various ‘families’ of proteins have been identified and

Author contributions

August B Smit: Conceptualization, Writing and editing, Supervision. Mazyar Abdollahi Nejat: Writing – original draft, Writing. Sabine Spijker: Visualization, editing. Remco Klaassen: Investigation, editing.

Conflict of interest statement

Nothing declared.

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