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PRESENTATION ON:
Glutamate and Glycine
Presented by: Under the guidence of
Mr.Mohd Khustar sirMohammad Muztaba
M.pharm, Pharmacology
1st year
INTEGRAL UNIVERSITY,lucknow
session: 2016-2017
•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.
• 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
Glutamate Receptor Subtypes
Glutamate
Recetor
Ionotropic
Receptor
Kainate
Receptor
NMDA
Recetor
AMPA
Receptor
Metabotro
pic
Receptor
Grope 1
mGlu 1
mGlu 5
Grope 2
mGlu 2
mGlu 3
Grope 3
mGlu 4
mGlu 6
mGl u7
mGlu 8
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 Ca2+
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
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:
1. NMDA Receptor (N-methyl-D-aspartate)
2. AMPA Receptor (amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)
3. Kainate Receptor
(named according to their specific agonists.)
NMDA Receptor
It is both voltage gated and ligand gated, (it requires co-activation
by 2 ligands glutamate and glycine.
• Activation of NMDA receptor is particularly effective in Ca2+ entry.
• They are readily blocked by Mg2+ (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
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 Ca2+ permeability
Agonists Antagonists
Glutamate
AMPA
Domoic acid
Ethanol
Tezampanel
Drugs act through AMPA receptors:
Kainate Receptor
•5 Subunits: GluK1-5
• Permeable to Na2+, K+ but less permeable to Ca2+
•Postsynaptically : Excitatory neurotransmission
•Presynaptically : Inhibitory neurotransmission (through GABA)
Agonists Antagonists
Glutamate
Kainate
Domoate
ethanol
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
Gq Gi/o
↑IP3/DAG,
↑se Ca2+
↓se cAMP
Somatode
ndric
Somatodendric and nerve
terminals
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
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 (Ca2+) to enter the cells. Ca2+ 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
GLYCINE
•It is simplest aminoacid
•Nonessential and glucogenic.
Formation of glycine:
1. From serine
2. From threonine
3. By glycine synthase reaction
By Glycine synthase:
NADH + + H+ NAD+
CO2 + NH4+ glycine
N5 , N10 –methylene THF THF
Glycine synthase is a multienzyme complex and
requires PLP , NAD and THF.
Metabolic functions of glycine:
Glycine is used for biosynthesis of
1. Heme
2. Purine ring
3. Creatine
4. Glutathione
5. As a conjugating agent
6. Glycine as neurotransmitter
7.Glycine as a constituent of protein
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
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
We hope you liked our presentation.
Thank you! 

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Glutamate muztaba

  • 1. PRESENTATION ON: Glutamate and Glycine Presented by: Under the guidence of Mr.Mohd Khustar sirMohammad Muztaba M.pharm, Pharmacology 1st 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
  • 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 Ca2+ 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: 1. NMDA Receptor (N-methyl-D-aspartate) 2. AMPA Receptor (amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) 3. 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. • Activation of NMDA receptor is particularly effective in Ca2+ entry. • They are readily blocked by Mg2+ (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 Ca2+ permeability
  • 11. Kainate Receptor •5 Subunits: GluK1-5 • Permeable to Na2+, K+ but less permeable to Ca2+ •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 Gq Gi/o ↑IP3/DAG, ↑se Ca2+ ↓se cAMP Somatode ndric 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 (Ca2+) to enter the cells. Ca2+ 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: 1. From serine 2. From threonine 3. By glycine synthase reaction
  • 16. By Glycine synthase: NADH + + H+ NAD+ CO2 + NH4+ glycine N5 , N10 –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 1. Heme 2. Purine ring 3. 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
  • 21. We hope you liked our presentation. Thank you! 