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NR2A (2A5S)
NR2A is a protein which forms an heterodimers channel with NR1 protein , the gathering of this two subnits formed NMDA receptors which is essential for Ca2+ influx in synapses thanks to glutamate and glycine binding essential for learning and memory. Variety of NR2 allows modulation of NMDAr.In the other hand, NMDA receptor is related to AMPA receptor in the same synapse.
Structure and FunctionNR2A (GluN2A) is composed of Amino-terminal domain (ATD), segments S1 and S2 which formed ligand binding domain of glutamate, three transmembrane helices (M1, M3,and M4), cytoplasmic re-entrant pore loop (M2), and an intracellular C-terminal domain (CTD).  Amino-terminal domain (ATD) The ATD is constitued by first 383 aminoacids of NR2A. ATD is an alpha and beta protein class. Structure is bilobed and form clam-shell like structure which consists in two lobes linked by a flexible hinge region defining a central groove. [1] Zn2+ may insert between 2 lobes and induces closure of channel by changing conformation of ATD. Zn increase affinity of glutamate on the LBD which reminds the desensization of AMPA and Kainate receptor. [2] ATD allow to modulate NMDA receptor. Difference between différents NR2 is mainly regulated by ATD because diversity of ATD can modulate traffic in endoplasmic reticulum ans then affect the localisation of NMDAr. ATD of NR2A increase glutamate affinity, control channel’s opening with high probability and open duration, control glutamate deactivationtime course.[3] [4] Ligand binding domain (LBD) LBD is constitued of two domains S1 (localised juste upstream M1 transmembranaire domain) and S2 and has affinity for glutamate or sometime glycine. Positive charge of Amino-group of the agonist bind to negativ charges residue of the pocket D731. In GlurR, negative charge amino acid is a E731 and is able to form salt bridge with agonist. In NR2A D731 is not able to do salt bridge with amino group because aspartate is one methylene lacking to do it. Amino group of agonist is stabilised by water mediated hydrogen bonds to amino acid E413 and Y761. The high affinity for glutamate agonist may be because of van der Walls contact between γ-carboxylate group of glutamate and Y730 of S2 domain which is conserved in NR2 protein. [5] Transmembrane domain The transmembrane domain is organized into 4 parts (from M1 to M4). M1 connects the N terminal domain to M2. M2 forms a reentrant loop contributing to the pore. The S1 segment of the N terminal domain intertwines with the S2 segment of the GlnBP-type domain in the extracellular loop M3 - M4 to form the glutamate binding pocket. On the other hand, desensitization of NMDA receptors is affected by residues near or inside the binding pocket as well as by residues in M2 that line the pore and the M3 loop - M4 is not responsible for the specificity of the NR2 subunit of glycine independent desensitization.[6] M2 loop is a channel-lining loop and located in transmembranaire domain. Two asparagines are located on N site of the domain and block Mg2+ and are permeable of Ca2+ [7] Ethanol acts as an inhibitor on NMDAr. Phenylalanine at position 639 in the M3 part of the transmembrane domain of NR2A interacts with the latter.[8]
CTD CTD domain is the less conserved of NR2 domain and like ATD allows différents localisation of NMDAr thanks to reticulum endoplasmic trafficking. It is indispensable to receptor surface dynamic and activation of specific signaling. CTD phosphorylation can modulate NMDAr, for instance it is useful for endocytosis during glutamate binding on LBD.[7] RegulationNR1/NR2A complexMutationsThe C-terminal truncation of NR2 subunits in NMDA receptors is an interesting mutation. Indeed, the C-terminal truncation of NR2A influences the functioning of the NMDA receptor. Several experiments were carried out and made it possible to conclude on this influence. First, mice with truncated NR2A subunits have been shown to still have a functional receptor channel, but NR2A ΔC / ΔC mice appear to be altered in the cellular signal transduction events involved in the induction of LTP (potentiation long-term). Despite the presence of the full-length NR2B subunit, the C-terminal truncation of the NR2A subunit altered the signal transduction mediated by NMDAR. Second, the C-terminal truncation of NR2A has been shown to alter fear in a particular setting. Indeed, the experiment was to put mutant and wild mice through stepwise avoidance training and put them in water. Thus, the researchers concluded that mutant mice have a significantly reduced latency time to leave the safe platform compared to wild mice and that mutant mice exhibit water balance deficits. The C-terminal truncation of NR2A therefore has consequences on synaptic plasticity and synaptic reorganization during the recording of hippocampal LTP, on the conditioning of fear and also on motor coordination. [9] NMDA receptors are inhibited by ethanol. Mutagenesis of an F residue in the transmembrane domain has made it possible to characterize the role of the latter in this inhibition. Structurally, there is a small loop of 150 amino acids between M3 and M4. On the other hand, the phenylalanine residue at position 639 is replaced by an alanine in the transmembrane domain (in part M3) and the results show significantly less inhibition by ethanol of NMDA compared to wild type receptors.[8] DiseaseAnti-nuclear antibodies produced in systemic or systemic lupus erythematosus (SLE, SLE) interact with the NR2A subunit of the NMDA receptor. This is because the Asp / Glu-Trp-Asp / Glu-Tyr-Ser / Gly pentapeptide is a molecular mimic of double-stranded DNA, so antibodies produced in a patient with SLE recognize this pentapeptide. The latter is also present in the structure of NR2A. Thus, these antibodies cross-interact with NR2A and therefore the NMDA receptor. This interaction can signal neuronal death by an excitotoxic mechanism. More generally, NMDA receptor dysfunction is implicated in multiple brain disorders, such as stroke, chronic pain, and schizophrenia. [10]
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