1 / 21

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

mason
Download Presentation

Glutamate

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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

More Related