Glutamatergic Neurotransmission <br />Srinath G<br />N N Rao<br />
Outline<br />Chemistry<br />Pathways<br />Clinical implications<br />
Chemistry<br />GSNAT<br />EAAT<br />
Two precursors for glutamate synthesis: α-ketoglutarate , glutamine<br />α-ketoglutarate	        L-Glutamate<br />GDH<br />
Glutamate Receptor Composition<br />Out<br />In<br />Subunits<br />{<br />NMDAR1<br />NMDAR2a<br />NMDAR2b<br />NMDAR2c<br...
AMPA receptor functional diversity<br />Mixing and matching of subunits (see GABA receptors for examples)<br />Further div...
Ion selectivity is modulated by RNA editing<br />Kandel, Schwartz, Jessel (2000) Principles of Neural Science 4ed<br />
NMDAR<br />
Co-incidence detection<br />
PSD<br />Silent synapse<br />
Metabotropic Glutamate Receptors (mGluR’s)<br />mGluR function: modulatory <br />Class C GPCR, very limited homology to rh...
mGluR Ligands<br />Glutamate binding site<br />Allosteric Ligand <br />binding site<br />Competitive Ligand binding site<b...
Allosteric
Positive modulator enhances response to glutamate
Negative modulator suppresses response to glutamate</li></ul>Modified : http://www.npsp.com/img/img_mGluR_diag.jpg<br />
mGlu5 receptor antagonists exhibit the widest and most robust anxiolytic activity <br />(MPEP (2-methyl-6-(phenylethynyl)-...
mGlu7 receptor is prominently expressed in the basal ganglia, its role in restoring motor function in animal models of Par...
Glycine<br />
Glycine- from Choline and L-Serine<br />L-Serine	       Glial cells<br />L-Serine	       Glycine<br />L-Serine	       D-Se...
Pathways in the brain<br />
Cortico-brainstem Mesolimbic Pathway<br />
Cortico-brainstem Mesocortical Pathway<br />
CSTC Loop<br />
Dopamine and Glutamate<br />
Serotonin and Glutamate<br />
Glutamate excitotoxicity<br />
Glutamate and Schizophrenia<br />
Glutamate and Schizophrenia<br />
Miscellaneous<br />Estrogen increases glutamate release<br />Serotonin increases glutamate release <br />
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Glutamate

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Glutamate

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