Calcium NMDA receptor activation

Other systems also interact with glutamate. Activation of L-type voltagegated calcium channels (VGCC) occurs with NMDA receptor activation. Lamotrigine blocks several ion channels, including P- and N-type VGCC channels, an action that blocks the euphoric effects of ketamine and reduces dysphoric and cognitive effects (Hundt et al. 1998). Other modulatory sites,... 

McDermott AB, Mayer ML, Westbrook GL NMDA receptors activation increased cytoplasmatic calcium concentration in cultured spinal cord neurones. Nature 321 519-522, 1986... 

This observation led to the finding that a soluble enzyme from rat forebrain catalyzes the NADPH-dependent formation of NO and L-citrulline from L-ar-ginine by calcium-dependent mechanisms (Knowles et al., 1989). A subsequent study revealed that glutamate and NMDA stimulate NO and L-citrulline formation in rat cerebellar slices and that this is associated with a concomitant stimulation of cyclic GMP formation (Bredt and Snyder, 1989), thus establishing a link between NMDA-receptor activation and cyclic GMP formation (Fig. 4). These investigators went on to purify and characterize NO synthase from cerebellum (Bredt and Snyder, 1990 Bredt et al., 1991) and to show the localization of NO synthase in the brain to discrete neuronal populations (Bredt et al., 1990). 

Furukawa, K., W. Fu, Y. Li, W. Witke, D.J. Kwiatkowski, and M.P. Mattson. 1997. The actin-severing protein gelsolin modulates calcium channel and NMDA receptor activities and vulnerability to excito-toxicity in hippocampal neurons. J Neurosci. 17 8178-86. 

Grb-2 facilitates the transduction of an extracellular stimulus to an intracellular signaling pathway, (b) The adaptor protein PSD-95 associates through one of its three PDZ domains with the N-methyl-D-aspartic acid (NMDA) receptor. Another PDZ domain associates with a PDZ domain from neuronal nitric oxide synthase (nNOS). Through its interaction with PSD-95, nNOS is localized to the NMDA receptor. Stimulation by glutamate induces an influx of calcium, which activates nNOS, resulting in the production of nitric oxide. 

These include nicotinic acetylcholine receptors, neuronal calcium channels, muscle sodium channels, vasopressin receptors, and iV-methyl-D-aspartate (NMDA) receptors. Some general features of the structure, function, and evolution of biologically active peptides isolated from Conus venom are presented. 

Figure 3.1 Schematic representation of a generic excitatory synapse in the brain. The presynaptic terminal releases the transmitter glutamate by fusion of transmitter vesicles with the nerve terminal membrane. Glutamate diffuses rapidly across the synaptic cleft to bind to and activate AMPA and NMDA receptors. In addition, glutamate may bind to metabotropic G-protein-coupled glutamate receptors located perisynaptically to cause initiation of intracellular signalling via the G-protein, Gq, to activate the enzyme phospholipase and hence produce inositol triphosphate (IP3) which can release Ca from intracellular calcium stores...

Figure 13.9 The production and actions of nitric oxide (NO). The influx of calcium through either calcium channels or NMDA receptors triggers NOS to convert L-arginine to NO. L-NAME and 7-NI inhibit this process. NO, once produced, can diffuse in a sphere and then can activate guanylate cyclase...

During ischaemia, NOS is activated by calcium influx or by cytokines like tumour necrosis factor (TNF) or by lipopolysaccharide (LPS) and NO is produced in excess. It has been proposed that the excitotoxic effect of glutamate, which contributes to ischaemia-induced neuronal damage, is mediated by increased production of NO via a chain of events that includes increases in intracellular calcium (via glutamate activation of NMDA receptors), calcium activation of NOS, production of NO and peroxynitrite, and induction of lipid peroxidation. In fact, N-nitro-L-atginine, a selective inhibitor of NOS, has been shown to prevent glutamate-induced neurotoxicity in cortical cell cultures (Dawson rf /., 1991). 

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