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Glutamate

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Presented in IMH, 2009

Presented in IMH, 2009

Published in: Health & Medicine

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Transcript

  • 1. Glutamatergic Neurotransmission
    Srinath G
    N N Rao
  • 2. Outline
    Chemistry
    Pathways
    Clinical implications
  • 3. Chemistry
    GSNAT
    EAAT
  • 4. Two precursors for glutamate synthesis: α-ketoglutarate , glutamine
    α-ketoglutarate L-Glutamate
    GDH
  • 5. Glutamate Receptor Composition
    Out
    In
    Subunits
    {
    NMDAR1
    NMDAR2a
    NMDAR2b
    NMDAR2c
    Na++
    NMDA
    K+
    Ca++
    {
    GLUR1
    GLUR2*
    GLUR3
    GLUR4
    Ca++
    AMPA
    Na++
    K+
    Na++
    {
    GLUR5
    GLUR6
    GLUR7
    KA1
    KA2
    KA
    K+
    Ca++
  • 6. AMPA receptor functional diversity
    Mixing and matching of subunits (see GABA receptors for examples)
    Further diversity generated by alternative splicing, editing
    Flip and flop splice forms desensitize at different rates, both have rapid onset kinetics
    (gluR2 homomers shown)
  • 7.
  • 8. Ion selectivity is modulated by RNA editing
    Kandel, Schwartz, Jessel (2000) Principles of Neural Science 4ed
  • 9. NMDAR
  • 10. Co-incidence detection
  • 11. PSD
    Silent synapse
  • 12. Metabotropic Glutamate Receptors (mGluR’s)
    mGluR function: modulatory
    Class C GPCR, very limited homology to rhodopsin
    mGluR’s are sub-divided based on sequence similarity
    Group I ( mGluR1 and mGluR5 )(Gq---PLC)
    Group II ( mGluR2 and mGluR3 )(Gi---AC)
    Group III ( mGluR4, mGluR6, mGluR7 and mGluR8 )(Gi---AC)
  • 13. mGluR Ligands
    Glutamate binding site
    Allosteric Ligand
    binding site
    Competitive Ligand binding site
    • Competitive
    • 14. Allosteric
    • 15. Positive modulator enhances response to glutamate
    • 16. Negative modulator suppresses response to glutamate
    Modified : http://www.npsp.com/img/img_mGluR_diag.jpg
  • 17. mGlu5 receptor antagonists exhibit the widest and most robust anxiolytic activity
    (MPEP (2-methyl-6-(phenylethynyl)-pyridine), a highly selective and brain-penetrant mGlu5 receptor antagonist)
    metabotropic glutamate receptor type 5 with the neuronal Ca2+-binding protein 2 modulates receptor function.
    activation of either mGlu(5) by positive allosteric modulators or stimulation of mGluR(2/3) receptors by agonists may offer new strategy in schizophrenia treatment.
  • 18. mGlu7 receptor is prominently expressed in the basal ganglia, its role in restoring motor function in animal models of Parkinson's disease are being tried
    selective mGlu3 receptor agonists or enhancers are potential candidates as neuroprotective agents in Parkinson's disease, and their use might circumvent the limitations associated with the administration of exogenous GDNF.
  • 19. Glycine
  • 20. Glycine- from Choline and L-Serine
    L-Serine Glial cells
    L-Serine Glycine
    L-Serine D-Serine
    D-Serine OH pyruvate
    LSerT
    Glial cell
    SHMT
    AMPA
    Na+
    THF
    Racemase
    Gly
    DAO
    GlyT1
    3Na+
  • 21.
  • 22. Pathways in the brain
  • 23. Cortico-brainstem Mesolimbic Pathway
  • 24. Cortico-brainstem Mesocortical Pathway
  • 25. CSTC Loop
  • 26. Dopamine and Glutamate
  • 27. Serotonin and Glutamate
  • 28. Glutamate excitotoxicity
  • 29. Glutamate and Schizophrenia
  • 30. Glutamate and Schizophrenia
  • 31. Miscellaneous
    Estrogen increases glutamate release
    Serotonin increases glutamate release
  • 32. Drugs
    Memantine-gating of blocked channels and binding to two sites on NMDA receptors
    PCP
    Ketamine
    Topiramate-inhibition of GluR5 kainate receptors could represent a key mechanism underlying the anticonvulsant activity of TPM
    Drugs in schizophrenia- Glutamate agonists or antagonists?
    Glycine agonists- d- cycloserine
  • 33. References
    Kaplan & Saddock- CTP 9th ed.
    Psychopharmacology- Stephen Stahl
    Psychiatry- Tasman- 3rd ed.
    Neuroscience- Purves
    www. Pubmed.com
  • 34. Thank you