Glutamatergic neurotransmission involves glutamate, the major excitatory neurotransmitter in the brain. There are two pathways for glutamate synthesis from precursors and multiple receptor types including NMDA, AMPA, KA, and metabotropic receptors. The different receptor subunits provide diversity in function. Glutamate signaling is involved in many brain pathways and clinical implications include roles in schizophrenia, Parkinson's disease, and drug mechanisms of action.

1. Glutamatergic Neurotransmission Srinath GN N Rao

2. OutlineChemistryPathwaysClinical implications

3. ChemistryGSNATEAAT

4. Two precursors for glutamate synthesis: α-ketoglutarate , glutamineα-ketoglutarate L-GlutamateGDH

5. Glutamate Receptor CompositionOutInSubunits{NMDAR1NMDAR2aNMDAR2bNMDAR2cNa++NMDAK+Ca++{GLUR1GLUR2*GLUR3GLUR4Ca++AMPANa++K+Na++{GLUR5GLUR6GLUR7KA1KA2KA K+Ca++

6. AMPA receptor functional diversityMixing and matching of subunits (see GABA receptors for examples)Further diversity generated by alternative splicing, editingFlip and flop splice forms desensitize at different rates, both have rapid onset kinetics(gluR2 homomers shown)

8. Ion selectivity is modulated by RNA editingKandel, Schwartz, Jessel (2000) Principles of Neural Science 4ed

9. NMDAR

10. Co-incidence detection

11. PSDSilent synapse

12. Metabotropic Glutamate Receptors (mGluR’s)mGluR function: modulatory Class C GPCR, very limited homology to rhodopsinmGluR’s are sub-divided based on sequence similarityGroup I ( mGluR1 and mGluR5 )(Gq---PLC)Group II ( mGluR2 and mGluR3 )(Gi---AC)Group III ( mGluR4, mGluR6, mGluR7 and mGluR8 )(Gi---AC)

13. mGluR LigandsGlutamate binding siteAllosteric Ligand binding siteCompetitive Ligand binding siteCompetitive

14. Allosteric

15. Positive modulator enhances response to glutamate

16. Negative modulator suppresses response to glutamateModified : 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 triedselective 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-SerineL-Serine Glial cellsL-Serine GlycineL-Serine D-SerineD-Serine OH pyruvateLSerTGlial cellSHMTAMPANa+THFRacemaseGlyDAOGlyT13Na+

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. MiscellaneousEstrogen increases glutamate releaseSerotonin increases glutamate release