Structural and Functional Architecture of AMPA-Type Glutamate Receptors and Their Auxiliary Proteins

Abstract

AMPA receptors (AMPARs) are tetrameric ion channels that together with other ionotropic glutamate receptors (iGluRs), the NMDA and kainate receptors, mediate a majority of excitatory neurotransmission in the central nervous system. Whereas NMDA receptors gate channels with slow kinetics, responsible primarily for generating long-term synaptic potentiation and depression, AMPARs are the main fast transduction elements at synapses and are critical for the expression of plasticity. The kinetic and conductance properties of AMPARs are laid down during their biogenesis and are regulated by post-transcriptional RNA editing, splice variation, post-translational modification, and subunit composition. Furthermore, AMPAR assembly, trafficking, and functional heterogeneity depends on a large repertoire of auxiliary subunits-a feature that is particularly striking for this type of iGluR. Here, we discuss how the subunit structure, stoichiometry, and auxiliary subunits generate a heterogeneous plethora of receptors, each tailored to fulfill a vital role in fast synaptic signaling and plasticity.

Neuropilin-2/PlexinA3 Receptors Associate with GluA1 and Mediate Sema3F-Dependent Homeostatic Scaling in Cortical Neurons

“…CUB domain-containing proteins, including SOL-1 and SOL-2 in C. elegans , and Netos 1 and 2 in mouse associate with glutamate receptors and regulate their channel properties and trafficking (Greger et al, 2016; Howe, 2015; Jackson and Nicoll, 2011; Straub and Tomita, 2012; Vernon and Swanson, 2017; Wang et al, 2012a). Similar to these proteins, the N-terminal portion of the Npn-2 extracellular domain harbors two CUB domains (Pasterkamp, 2012).…”

“…We found that Npn-2 coimmunoprecipitates most robustly with GluA1, and to a much lesser extent with GluA2 (Figure 5A). Npn-2 does not coimmunoprecipitate with other glutamate receptors, including the kainate receptor subunit GluK2, which interacts with the CUB domain-containing transmembrane proteins Neto1 and Neto2, or the NMDAR subunit NR2A, which interacts with Neto1 (Greger et al, 2016; Howe, 2015; Jackson and Nicoll, 2011; Straub and Tomita, 2012; Vernon and Swanson, 2017; Wang et al, 2012a). (Figures 5A and 5B).…”

“…Since the Neto protein CUB domains mediate interactions between Neto1 and Neto2 and the GluK2 kainate receptor (Greger et al, 2016; Howe, 2015; Jackson and Nicoll, 2011; Straub and Tomita, 2012; Vernon and Swanson, 2017; Wang et al, 2012a), we next used Npn-2 ectodomain deletion mutants (Figures 7A and 7B) to map extracellular protein domains required for Npn-2 interactions with GluA1. We transfected 293T cells with individual Npn-2 deletion constructs and GluA1 and assessed their association.…”

“…Several CUB domain-containing proteins interact with various neurotransmitter receptors and regulate channel localization, trafficking and biophysical properties. The C. elegans CUB domain-containing proteins SOL-1 and SOL-2 regulate glutamate receptor channel properties, C. elegans LEV-10 mediates AChR clustering, Drosophila Neto interacts with iGluRs and participates in clustering glutamate receptors at the NMJ, and mammalian Neto1 and Neto2 are well-characterized kainate and NMDA glutamate receptor auxiliary subunits that associate with these neurotransmitter receptors through their CUB domains and regulate receptor channel properties (Greger et al, 2016; Howe, 2015; Jackson and Nicoll, 2011; Straub and Tomita, 2012; Vernon and Swanson, 2017; Wang et al, 2012a). Vertebrate Neto proteins also directly contribute to kainate receptor surface expression and synaptic localization, though each of the Neto1 and Neto2 CUB domains appear to contribute in a somewhat additive fashion to glutamate receptor binding.…”

“…Transmembrane A MPAR r egulatory p roteins (TARPs), along with other auxiliary subunits, serve to regulate synaptic AMPAR synaptic targeting, channel conductance and other aspects of receptor properties (Jackson and Nicoll, 2011). Several c omplement C 1r/c1s, Uegf, Bmp1 (CUB) domain-containing transmembrane proteins, including SOL-1, SOL-2 and LEV-10 in C. elegans, Neto in Drosophila, and Neto1 and Neto2 in rodents, interact with a variety of neurotransmitter receptors to regulate their trafficking and function (Greger et al, 2016; Howe, 2015; Jackson and Nicoll, 2011; Straub and Tomita, 2012; Vernon and Swanson, 2017; Wang et al, 2012a). It remains to be determined if any of these CUB domain proteins are themselves regulated by extracellular signals.…”