The C‐terminal domains of the NMDA receptor: How intrinsically disordered tails affect signalling, plasticity and disease

Abstract

NMDA receptors are part of the ionotropic glutamate receptor family, and are crucial for neurotransmission and memory. At the cellular level, the effects of activating these receptors include long-term potentiation (LTP) or depression (LTD).The NMDA receptor is a stringently gated cation channel permeable to Ca 2+ , and it shares the molecular architecture of a tetrameric ligand-gated ion channel with the other family members. Its subunits, however, have uniquely long cytoplasmic C-terminal domains (CTDs). While the molecular gymnastics of the extracellular domains have been described in exquisite detail, much less is known about the structure and function of these CTDs. The CTDs vary dramatically in length and sequence between receptor subunits, but they all have a composition characteristic of intrinsically disordered proteins. The CTDs affect channel properties, trafficking and downstream signalling output from the receptor, and these functions are regulated by alternative splicing, protein-protein interactions, and post-translational modifications such as phosphorylation and palmitoylation. Here, we review the roles of the CTDs in synaptic plasticity with a focus on biochemical mechanisms. In total, the CTDs play a multifaceted role as a modifier of channel function, a regulator of cellular location and abundance, and signalling scaffold control the downstream signalling output.

Splicing and editing of ionotropic glutamate receptors: a comprehensive analysis based on human RNA-Seq data

“…S20B), but the corresponding splice sites are absent in rat and mouse, which supports the suggestion that this is a primate-specific isoform [139]. Shortening of the GluN2A CTD should have important functional consequences, as it results in a loss of several interaction motifs, including CaMKII and PSD-95 binding sites [27,122]. We did not identify any other relevant splice junctions belonging to GRIN2A.…”

“…AMPA receptor flip/flop splicing, for instance, affects gating by modifying this LBD dimer interface and the linker region, which connects the LBDs to the TMD [20,26]. Most described splice events, however, affect the CTDs, which mediate interactions with other synaptic proteins and which are extensively controlled by post-translational modifications [8,9,11,27]. Alteration of the CTDs has also important consequences for receptor trafficking and turnover (e.g., [28][29][30]).…”

The emerging role of kainate receptor functional dysregulation in pain

“…There are three main classes of iGluRs which are structurally and pharmacologically different: NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid) and kainate (KA) receptors. 5 , 6 NMDA receptors are important for initiating long-term neuronal plasticity such as long-term potentiation, 7 , 8 whereas AMPA receptors control fast excitatory synaptic transmission and plasticity. 9 , 10 Both of these receptors were found to be associated with pain development, and both NMDA and AMPA receptor antagonists were aid in the treatment of pain.…”

Introducing the special issue on “Proteins and Circuits in Memory”

“…Molecular clues suggest that the tail is intrinsically disordered, which makes it part of a large family of channels that are tuned by such disordered chains (Kjaergaard & Kragelund, 2017). Warnet et al (2020) review the functions of the C‐terminal domains of the NMDA receptor in light of their intrinsically disordered nature covering its involvement in signalling, plasticity and disease.…”