Glutamate muztaba

GLUTAMATE AND GLYCIN

1. PRESENTATION ON: Glutamate and Glycine Presented by: Under the guidence of Mr.Mohd Khustar sir Mohammad Muztaba M.pharm , Pharmacology 1 st year INTEGRAL UNIVERSITY,lucknow session: 2016-2017

2. Glutamate is widely distributed excitatory neurotransmitter in the CNS, where its concentration is much higher than in other tissues. Synthesized within the brain from: Glucose (via Kreb’s cycle / α - ketoglutarate ) Glutamine (from glial cells) Glutamate is a precursor of GABA which is inhibitory neurotransmitter in the CNS. They are produced in the mitochondria, transported into the cytoplasm, and packaged into synaptic vesicles.

3. It acts through both ligand gated ion channel ( ionotropic receptor) and G-protein coupled receptor ( Metabotropic receptor) Transport of Glutamate ( Glu ) and Glutamine ( Gln ) by neurons and astrocytes Released Glutamat is captured partly by neurons and partly by astrocytes , which convert most of it into the glutamine. EAAT : Excitatory amino acid transporter GlnT : Glutamine transporter VGluT : Vesicular glutamate transporter 3

4. Glutamate Receptor Subtypes Glutamate Recetor Ionotropic Receptor Kainate Receptor NMDA Recetor AMPA Receptor Metabotropic Receptor Grope 1 mGlu 1 mGlu 5 Grope 2 mGlu 2 mGlu 3 Grope 3 mGlu 4 mGlu 6 mGl u7 mGlu 8

5. Ionotropic Glutamate Receptor Ionotropic Glutamate receptors are ligand gated type of ion channels and get activates when ligand gets bind to the receptor. All of the ionotropic glutamate receptors are nonselective cation channels, allowing the passage of Na +  and K + , and in some cases small amounts of Ca 2+ Upon binding, the agonist will stimulate direct action of the central pore of the receptor, an ion channel, allowing ion flow and causing excitatory postsynaptic current (EPSC). This current is depolarizing and, if enough glutamate receptors are activated, may trigger an action potential in the postsynaptic neuron. All produce excitatory postsynaptic current, but the speed and duration of the current is different for each type.

6. 6 Binding study shows that ionotropic glutamate receptots are most abundant in cortex , basal ganglia and sensory pathways . NMDA and AMPA receptors generally co-localised, but kainate receptors have a much more restricted distribution. Three main subtypes of Ionotropic Glutamate Receptor: NMDA Receptor ( N-methyl-D- aspartate ) AMPA Receptor ( amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) Kainate Receptor (named according to their specific agonists.)

7. NMDA Receptor It is both voltage gated and ligand gated, (it requires co-activation by 2 ligands glutamate and glycine .

8. 8 Activation of NMDA receptor is particularly effective in Ca 2+ entry. They are readily blocked by Mg 2+ (voltage dependance ) Glycine and Glutamate both require for NMDA receptor activation, binding site of both are different and both have to be occupied for the channel to open. Subunits: GluN1, GluN2A-D, GluN3A-B Drugs act through NMDA receptors: Agonists Antagonists Cycloserine Aspartate NMDA Ketamine Phencyclidine methadone Dexomethorphan Pethidine Nitrous oxide Acamprosate Amantadine Memantine

9. AMPA Receptor 4 types of subunits: GluA1-4 AMPA receptors have 4 types to which agonist can bind one for each subunit. The channel gets open when ligand gets bind to the extracellular transmembrane domains which then moves towards each other. To open the channel their should be two sites occupied over the receptor. Fast excitatory synaptic transmission AMPA permeable to calcium and other cations such as sodium potassium. Channel possessing GluR2A subunit: low Ca 2+ permeability

10. 10 Agonists Antagonists Glutamate AMPA Domoic acid Ethanol Tezampanel Drugs act through AMPA receptors:

11. 11 Kainate Receptor 5 Subunits: GluK1-5 Permeable to Na 2+, K + but less permeable to Ca 2+ Postsynaptically : Excitatory neurotransmission Presynaptically : Inhibitory neurotransmission (through GABA) Agonists Antagonists Glutamate Kainate Domoate ethanol

12. Metabotropic Glutamate Receptor The metabotropic glutamate receptors, or mGluRs , are a type of glutamate receptor that are active through an indirect metabotropic process. Classification Group 1 Group 2 mGlu 1, mGlu 5 mGlu 2, mGlu 3 G q G i /o ↑IP3/DAG, ↑se Ca 2+ ↓se cAMP Somatodendric Somatodendric and nerve terminals

13. Group 1 Group 2 Agonist DHPG CHPG LY354740 Antagonist LY367385 S-4-CPG LY341495 Group 1 receptor are located postsynaptically and are largely excitatory. Group 2 and Group 3 are presynaptic : activation tends to reduce synaptic transmission and neuronal excitability

14. Excitotoxicity Excitotoxicity is the pathological process by which nerve cells are damaged or killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate ( gutamate receptors) such as the NMDA receptors and AMPA receptors are overactivated by glutamatergic storm. Excitotoxins like NMDA and kainic acid which bind to these receptors, as well as pathologically high levels of glutamate, can cause excitotoxicity by allowing high levels of calcium ions (Ca 2+ ) to enter the cells. Ca 2+ influx into cells activates a number of enzymes, including phospholipase , endonucleases structures such as components of the cytoskeleton, membrane and DNA. Excitotoxicity can be involved in following diseases: Spinal cord injury Multiple sclerosis Alzheimer’s disease Parkinson’s disease Huntington's disease alcoholism

15. GLYCINE It is simplest aminoacid Nonessential and glucogenic . Formation of glycine : From serine From threonine By glycine synthase reaction

16. By Glycine synthase : NADH + + H + NAD + CO2 + NH4 + glycine N 5 , N 10 –methylene THF THF Glycine synthase is a multienzyme complex and requires PLP , NAD and THF.

17. Metabolic functions of glycine: Glycine is used for biosynthesis of Heme Purine ring Creatine 4. Glutathione 5. As a conjugating agent 6. Glycine as neurotransmitter 7.Glycine as a constituent of protein

18. 6.Glycine as neurotransmitter: It is a neurotransmitter in the brainstem and spinal cord. At moderate levels it disrupts neuronal traffic; but at very high levels it causes overexcitation

19. 7.Glycine as a constituent of protein It is seen where the polypeptide chain bends or turns. In collagen , every third aminoacid is glycine.

20. 20 Any question ?

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