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Glutamate

Novel Treatment of Excitotoxicity: Targeted Disruption of Intracellular Signalling From Glutamate Receptors. Glutamate. Excitotoxicity. Glutamate receptor and excitotoxicity. Types of Glutamate receptor. mGluRs. G-protein-coupled membrane receptors

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Glutamate

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  1. Novel Treatment of Excitotoxicity: Targeted Disruption ofIntracellular Signalling From Glutamate Receptors

  2. Glutamate

  3. Excitotoxicity

  4. Glutamate receptor and excitotoxicity • Types of Glutamate receptor

  5. mGluRs • G-protein-coupled membrane receptors • Downregulate K+ channel and upregulate non-selection cation channel • Inhibit GABA receptor activity and potentiate iGluR function • Mediate neuronal plasticity, nociception, pain and neurodegeneretion

  6. iGluRs • Ligand-gated ion channels, permeable to Na+, K+ or Ca2+ • Mediate synaptic plasticity • related to much of the toxicity induced by glutamate

  7. AMPA receptors • Permeable to Na+, K+ • Also permeable to Ca2+ unless it contain GluR2 • Loss of GluR2 implicated in delayed death of neurones in ischemia Structure of GluR2

  8. NMDA receptors • Highly permeable to Ca2+ and Na+ • Calcium transients responsible for the physiologic effects of NMDAR signalling • Calcium transients also trigger excitotoxic death

  9. Kainate receptors • Share many of the same structural characteristics as NMDA and AMPA receptors • Until recently, little was known about the functional and physiological roles of kainate receptors in the mammalian CNS

  10. Calcium and neurotoxicity • Localised increases in [Ca2+]i trigger physiological events • Excessive Ca2+ loading activates processes that lead to cell death • Neurotoxicity mediated by glutamate receptors is largely calcium dependent

  11. Calcium and neurotoxicity • Calcium load hypothesis Neurodegeneration is simply a function of the quantity of entering the cell However, some studies show that the calcium channel blockers can prevent Ca2+ accumulation but not neurotoxicity during anoxia

  12. Calcium and neurotoxicity • Source specific hypothesis Ca2+ toxicity occurs not simply as a function of increased Ca2+ concentration, but is instead linked to the route of Ca2+ entry and the distinct second messenger pathways that are activated as a result. Showing that Ca2+ loads produced by voltage-sensitive Ca2+ channels were not harmful whereas similar [Ca2+]i increases via NMDARs were toxic

  13. Postsynaptic organisation • Postsynaptic density (PSD) PSD is a multiprotein complex containing membrane proteins, signaling molecules and core PSD proteins

  14. Postsynaptic organisation • Membrane receptors and proteins mGluRs, iGluRs Cell junction protein

  15. Postsynaptic organisation • Enzymes and modulators Src-kinase, CaMKII, PKC , phosphatase calcineurin nNOS, SPAR, SynGAP

  16. Postsynaptic organisation • Cytoskeletal and scaffolding proteins actin, fodrin, tubulin and neurofilaments Spectrin, -actinin-2, AKAP 79 and PDZ-containing protein

  17. Neurotoxic signalling by glutamate receptors within the PSD • Neurotoxic effects of AMPAR signalling GluR2 hypothesis

  18. Neurotoxic signalling by glutamate receptors within the PSD • Neurotoxic effects of NMDAR signalling Role of PSD-95

  19. Targeting intracellular signal pathways • Strategies for treating excitotoxic damage • NMDAR and AMPAR blockers? • Particular receptor subunits antagonists • Low affinity blockers • Targeting the specific intracellular signal pathways and uncoupling glutamate receptors from their potentially neurotoxic downstream effectors

  20. Future directions • Limitations of the use of peptides and small proteins • Protein tranduction domains • Cross cell membranes independent of specific receptors or transporters • Ensure efficient delivery of attatched proteins into cells and across the BBB • Particularly suited to the narrow therapeutic window offered during stroke

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