Glutamate, the most abundant excitatory neurotransmitter in the vertebrate brain, targets two receptor families: ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). The iGluRs are responsible for both synaptic transmission and synaptic plasticity, are central to molecular mechanisms of learning and memory, and form tetrameric ligand-gated channel pores that allow the influx of Na+ and Ca2+ when glutamate binds to the extracellular ligand-binding domain (LBD). iGluRs can be further subdivided into N-methyl-D-aspartate (NMDA) receptors, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and kainate receptors. iGluRs form a dimer-of-dimers assembly, with individual subunits arranged in three main layers: the distal amino-terminal domain (ATD) on the ‘top’, the ligand-binding domain (LBD) sandwiched in the ‘middle’ and the transmembrane domain (TMD), harboring the ion channel, on the ‘bottom’. Prolonged stimulation of the iGluRs and other post-synaptic signaling components results in a phenomenon called excitotoxicity – a major contributor to NDDs and nervous system injuries. Reactive oxygen species (ROS) and overstimulation of calcium-dependent signaling molecules is responsible for neuronal cell death by a similar mechanism as outlined for nervous system trauma.


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