glutamate receptor
TRANSCRIPT
Glutamate Receptor
Prepared by: Anagha B. Patil M.Pharm (Sem-II) Department of Pharmacology Poona College of Pharmacy
• L- 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. 2
• 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
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Glutamate Receptor SubtypesGlutamate Recetor
Ionotropic ReceptorKainate Receptor
NMDA Recetor
AMPA Receptor
Metabotropic ReceptorGrope 1mGlu 1
mGlu 5
Grope 2mGlu 2
mGlu 3
Grope 3 mGlu 4
mGlu 6
mGl u7
mGlu 8
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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+
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 depolarizingand, 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.
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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.)
• 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.
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NMDA Receptor
It is both voltage gated and ligand gated, (it requires co-activation by 2 ligands glutamate and glycine.
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• 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
CycloserineAspartate
NMDA
KetaminePhencyclidine
methadoneDexomethorphan
PethidineNitrous oxideAcamprosateAmantadine Memantine
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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
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• 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
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Agonists Antagonists
GlutamateAMPA
Domoic acidQuisqualate
NBQXEthanol
Tezampanel
Drugs act through AMPA receptors:
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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
GlutamateKainate
Domoate
NBQXACET
ethanol
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Metabotropic Glutamate Receptor• The metabotropic glutamate receptors, or mGluRs, are a type of
glutamate receptor that are active through an indirect metabotropic process.
• Class C, G-Protein coupled receptor.
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Classification
Group 1 Group 2 Group 3
mGlu 1, mGlu 5 mGlu 2, mGlu 3 mGlu4, mGlu6-8
Gq Gi/o Gi/o
↑IP3/DAG, ↑se Ca2+ ↓se cAMP ↓se cAMP
Somatodendric Somatodendric and nerve terminals
Nerve terminals
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• 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
Group 1 Group 2 Group 3
Agonist DHPGCHPG
LY354740 L-AP4
Antagonist LY367385S-4-CPG
LY341495 CPPG
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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 injuryMultiple sclerosisAlzheimer’s diseaseParkinson’s diseaseHuntington's diseasealcoholism
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REFERENCES
H. P Rang, M. M. Dale, Rang and Dale’s Pharmacology, Amino Acid Transmitters, page no 448-453
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