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Guided by:
PROF.B VEERESH
Prepared by:
Mukul Tambe
G.Pulla Reddy College Of Pharmacy
Hyderabad. 5000024 (Telanaga)
2016-2018
1
CONTENTS
1. Introduction
2. Definition
3. Synthesis
4. Transporters
5. Receptors
6. Role in disease
7. Conclusion
2
3
4
 Also called as “GLUTAMIC ACID”.
L-Glutamate is a widely distributed
“EXCITATORY NEUROTRANSMITTER”,
in the CNS where its concentration
is much higher than in other tissues.
5
 It is an amino acid used throughout
the body for building up of proteins.
Energy metabolism .
It is found throughout the brain .
 “KING” of neurotransmitters.
Concentration is 10mM, highest of all AA & NT’s.
Involved in many behavioural and physiological functions.
6
SYNTHESIS
TRANSPORTERS…
7
 The neuronal presynaptic reuptake pump (EAAT or
excitatory amino acid transporter), Glutamate is transported
across membranes of synapse by these Na++ dependent
transporters.
These are 5 types
EAAT1 Astrocyte.
EAAT2 Astrocytes, Forebrain.
EAAT3 Upper motor neurons.
EAAT4 Cerebellar purkinje cells.
EAAT5 Retina.
Of these EAAT1 & 2 are involved in the reuptake and release
of glutamate during glutamine cycle.
RECEPTORS
8
9
GLUTAMATE RECEPTORS:
10
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.
11
12
IONOTROPIC GLUTAMATE
RECEPTORS
AMPA
KAINATE
NMDA
13
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.
•AMPA permeable to calcium and other cations such as
sodium potassium.
14
•Ca2+ /Calmoduline dependant protein kinase:
Ca2+
binds to calmoduline protein
it inturns activates protein kinase like CAM kinase,
which affects AMPA receptors in 2 ways
Phosphorelates AMPA receptor already
present in dendritic spine membrane
↑se their conductance to Na2+
Promote intracellular receptor
to move towards membrane
making more receptors
available to stimulate spine
LONG TERM
POTENTIATION
15
AMPA .
16
Kainate Receptor
•5 Subunits: GluK1-5
• Permeable to Na2+, K+ but less permeable to Ca2+
•Postsynaptically : Excitatory neurotransmission
•Presynaptically : Inhibitory neurotransmission
(through GABA)
KAINATE .
17
NMDA Receptor
It is both voltage gated and ligand gated, (it
requires co-activation by 2 ligands glutamate
and glycine.
18
• 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
*Agonists * Antagonists
-aspartate -ketamine
-cycloserine -pethidine
-NMDA -amantadine
- nitrous oxide
19
AMPA receptorsNMDA
receptor
Na+Na+Na+Na+
Ca2+
synaptic
strengthening With low presynaptic activity only some of the AMPA
receptors are activated, giving rise to a weak EPSP.
Under these circumstances the NMDA receptor is
inactive despite binding of glutamate because its
channel is blocked by Mg .2+
With high presynaptic activity most of the AMPA
receptors are activated and the EPSP is strong.
Mg2+
The Ca signal ultimately leads to synaptic
strengthening.
2+
The strong EPSP (or back-propagated action potential)
lifts the Mg block of the NMDA receptor.2+
2020
Metabotropic glutamate receptors
Group 1 Group 2 & 3
mGluR 1,5
Activate phospolipase C
Through Gq Protein
Predominantly located
postsynaptically.
mGluR 2,3 & mGluR 6,7,8
Inhibit adenylyl cyclase
Through Gi Protein
Predominantly located
presynaptically as Auto
receptors.
21
22
g
b
a
G-protein coupled receptors
Cell membrane
• G-protein composed of one
alpha, beta, and gamma subunit
• 2 primary signaling cascades:
cAMP or phosphatidylinositol
pathways.
• Pathway activated depends on
alpha subunit type
• GDP bound to a when
inactive.
g
b
a
23
g
b
a
Contd..
Cell membrane
• When a ligand binds, the receptor
changes conformation, allowing G-
protein to be activated (GDP is
exchanged for GTP)
• G-protein dissociates from receptor
then subunits from each other.
GTP
a
GTP
24
g
b
a
Contd..
Cell membrane
GTP
a
GTP
• Gαi binds to AC and inhibits cAMP
synthesis
25
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 .
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
Alzheimer’s disease
Parkinson’s disease etc.
26
Physiological or Pathological
Roles…..
*AMPA receptors
Mediate most fast EPSPs in the CNS
*Kainate receptors
Regulation of neuronal excitability
Epilepsy, Excitotoxicity and Pain
*NMDA receptors
Mediate most fast EPSPs in the CNS
Anaesthesia
Learning and memory
Developmental plasticity
Epilepsy
Excitotoxicity (eg :- Stroke)
Schizophrenia
27
28
29
REFERENCES
H.P Rang, M. M. Dale, Rang and Dale’s Pharmacology, Amino Acid
Transmitters, page no 448-453
Rang & Dale’s Pharmacology.
slideshare.net/AnaghaPatil5/glutamate-receptor
30

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Glutamate recp

  • 1. Guided by: PROF.B VEERESH Prepared by: Mukul Tambe G.Pulla Reddy College Of Pharmacy Hyderabad. 5000024 (Telanaga) 2016-2018 1
  • 2. CONTENTS 1. Introduction 2. Definition 3. Synthesis 4. Transporters 5. Receptors 6. Role in disease 7. Conclusion 2
  • 3. 3
  • 4. 4  Also called as “GLUTAMIC ACID”. L-Glutamate is a widely distributed “EXCITATORY NEUROTRANSMITTER”, in the CNS where its concentration is much higher than in other tissues.
  • 5. 5  It is an amino acid used throughout the body for building up of proteins. Energy metabolism . It is found throughout the brain .  “KING” of neurotransmitters. Concentration is 10mM, highest of all AA & NT’s. Involved in many behavioural and physiological functions.
  • 7. TRANSPORTERS… 7  The neuronal presynaptic reuptake pump (EAAT or excitatory amino acid transporter), Glutamate is transported across membranes of synapse by these Na++ dependent transporters. These are 5 types EAAT1 Astrocyte. EAAT2 Astrocytes, Forebrain. EAAT3 Upper motor neurons. EAAT4 Cerebellar purkinje cells. EAAT5 Retina. Of these EAAT1 & 2 are involved in the reuptake and release of glutamate during glutamine cycle.
  • 10. 10 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.
  • 11. 11
  • 13. 13 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. •AMPA permeable to calcium and other cations such as sodium potassium.
  • 14. 14 •Ca2+ /Calmoduline dependant protein kinase: Ca2+ binds to calmoduline protein it inturns activates protein kinase like CAM kinase, which affects AMPA receptors in 2 ways Phosphorelates AMPA receptor already present in dendritic spine membrane ↑se their conductance to Na2+ Promote intracellular receptor to move towards membrane making more receptors available to stimulate spine LONG TERM POTENTIATION
  • 16. 16 Kainate Receptor •5 Subunits: GluK1-5 • Permeable to Na2+, K+ but less permeable to Ca2+ •Postsynaptically : Excitatory neurotransmission •Presynaptically : Inhibitory neurotransmission (through GABA) KAINATE .
  • 17. 17 NMDA Receptor It is both voltage gated and ligand gated, (it requires co-activation by 2 ligands glutamate and glycine.
  • 18. 18 • 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 *Agonists * Antagonists -aspartate -ketamine -cycloserine -pethidine -NMDA -amantadine - nitrous oxide
  • 19. 19 AMPA receptorsNMDA receptor Na+Na+Na+Na+ Ca2+ synaptic strengthening With low presynaptic activity only some of the AMPA receptors are activated, giving rise to a weak EPSP. Under these circumstances the NMDA receptor is inactive despite binding of glutamate because its channel is blocked by Mg .2+ With high presynaptic activity most of the AMPA receptors are activated and the EPSP is strong. Mg2+ The Ca signal ultimately leads to synaptic strengthening. 2+ The strong EPSP (or back-propagated action potential) lifts the Mg block of the NMDA receptor.2+
  • 20. 2020 Metabotropic glutamate receptors Group 1 Group 2 & 3 mGluR 1,5 Activate phospolipase C Through Gq Protein Predominantly located postsynaptically. mGluR 2,3 & mGluR 6,7,8 Inhibit adenylyl cyclase Through Gi Protein Predominantly located presynaptically as Auto receptors.
  • 21. 21
  • 22. 22 g b a G-protein coupled receptors Cell membrane • G-protein composed of one alpha, beta, and gamma subunit • 2 primary signaling cascades: cAMP or phosphatidylinositol pathways. • Pathway activated depends on alpha subunit type • GDP bound to a when inactive. g b a
  • 23. 23 g b a Contd.. Cell membrane • When a ligand binds, the receptor changes conformation, allowing G- protein to be activated (GDP is exchanged for GTP) • G-protein dissociates from receptor then subunits from each other. GTP a GTP
  • 24. 24 g b a Contd.. Cell membrane GTP a GTP • Gαi binds to AC and inhibits cAMP synthesis
  • 25. 25 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 . 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 Alzheimer’s disease Parkinson’s disease etc.
  • 26. 26
  • 27. Physiological or Pathological Roles….. *AMPA receptors Mediate most fast EPSPs in the CNS *Kainate receptors Regulation of neuronal excitability Epilepsy, Excitotoxicity and Pain *NMDA receptors Mediate most fast EPSPs in the CNS Anaesthesia Learning and memory Developmental plasticity Epilepsy Excitotoxicity (eg :- Stroke) Schizophrenia 27
  • 28. 28
  • 29. 29 REFERENCES H.P Rang, M. M. Dale, Rang and Dale’s Pharmacology, Amino Acid Transmitters, page no 448-453 Rang & Dale’s Pharmacology. slideshare.net/AnaghaPatil5/glutamate-receptor
  • 30. 30