Glutamate Receptor Excitotoxicity Kills Neurons

Neurons communicate by neurotransmission at synapses (Fig. 2A). In the CNS, the amino acid glutamate is the major excitatory neurotransmitter that is packaged into small clear synaptic vesicles (Fig. 2A). Glutamate is released from nerve terminals into the synaptic cleft by regulated exocytosis of synaptic vesicles (Fig. 2B). Concentrations of glutamate at the synaptic cleft have been estimated to be approximately 1 mM, whereas the concentration of interstitial glutamate is about 1 mM. Glutamate can bind and activate several types of glutamate receptors (GluRs) on neurons (Table VII). These GluRs are classified broadly as either ion channel or metabotropic G-protein-coupled receptors. These classes of GluRs have distinct molecular compositions and distinct signal transduction mechanisms.

The ion channel GluRs are the N-methyl-D-aspar-tate (NMDA) receptors and the non-NMDA receptors. The non-NMDA GluRs are further divided into the a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and kainate (KA) receptors (Table VII). The ion channel GluRs all form monovalent cation (Na + , K+) conducting channels, but they have differences in their permeabilities to divalent cations (Ca2+). The activation of ion channel GluRs directly changes the conductance of specific ions through the receptor-ion channel complex, thereby inducing membrane depolarization. Fast, short-lived (1-10 msec) excitatory postsynaptic currents in most neurons in the CNS are mediated by these receptors. These receptors are oligomers, most likely pentameric heterooligo-mers, of homologous subunits encoded by distinct genes. The NMDA receptor subunits are NR1, NR2A-NR2D, and NR3, the AMPA receptor sub-units are GluR1-GluR4 (or GluRA-GluRD), and the kainate receptor subunits are GluR5-GluR7 and KA1-KA2.

The metabotropic GluRs (mGluRs) are G-protein-coupled receptors that are single proteins encoded by

Table VII

Molecular Classification of Glutamate Receptors

Table VII

Molecular Classification of Glutamate Receptors

Understanding And Treating Autism

Understanding And Treating Autism

Whenever a doctor informs the parents that their child is suffering with Autism, the first & foremost question that is thrown over him is - How did it happen? How did my child get this disease? Well, there is no definite answer to what are the exact causes of Autism.

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