PRESENTATION ON GLUTAMATE RECEPTORS

PRESENTED TO PRESENTED BY TALAH JAWAID SIR CHETAN RASTOGI

Glutamate These are Excitatory Amino Acid.

Principal excitatory neurotransmitter in CNS, stored in

neuronal cell membrane.

Glutamate comes into the CNS mainly by glial cells and by

Kreb’s cycle.

Responsible for neural communication, memory formation,

learning, and regulation

GLUTAMATE SYNTHESIS

Glutamine comes from glial cells in the neurons.  

In the neurons the glutamine is converted into glutmate

with the help of glutaminase enzyme.

  Glutamate is stored in the synaptic vesicles. 

From synaptic vesicles glutamate release by the

process of exocytosis which is Ca dependent.⁺

GLUTAMATE SYNTHESIS

Glutamate ReceptorsGlutamate receptors are synaptic receptors located primarily on the membranes of neuronal cells.

Glutamate (glutamic acid) is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the body's most prominent neurotransmitter, the brain's main excitatory neurotransmitter, and also the precursor for GABA, the brain's main inhibitory neurotransmitter.

Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.

Ligand gated non-selective cation channels.  Allows flow of K , Na and sometimes Ca in ⁺ ⁺ ⁺response to glutamate binding.

 

Ionotropic receptors

IONOTROPIC GLUTAMATE RECEPTORS

AMPA

KAINATE

NMDA

• The NMDA receptor (NMDAR), a glutamate receptor, which plays role in long term potentiation in learning and memory.

• The NMDAR is a specific type of ionotropic glutamate receptor. NMDA (N-methyl-D-aspartate) is the name of a selective agonist that binds to NMDA receptors but not to other 'glutamate' receptors.

THE NMDA RECEPTOR(N-methyl-D-aspartate)

• Calcium flux through NMDARs is thought to be critical in synaptic plasticity, a cellular mechanism for learning and memory.

• Aminocyclopropanecarboxylic acid• D-Cycloserine• cis-2,3-Piperidinedicarboxylic acid• L-aspartate• Quinolinate• Homocysterate• D-serine• ACPL• L-alanine• GLYX-13

NMDA receptor agonists

Partial agonists

• N-Methyl-D-aspartic acid (NMDA)• 3,5-dibromo-L-phenylalanine

NMDA receptor antagonist• Amantadine• Ketamine• Methoxetamine• Phencyclidine (PCP)• Nitrous oxide• Dextromethorphan and dextrorphan• Memantine• Ethanol• Riluzole • Xenon• HU-211 (also a cannabinoid)• Lead • Conantokins• Huperzine A• Atomoxetine

AMPA Receptors

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

receptor (also known as AMPA receptor, AMPAR, orquisqualate

receptor) is a non-NMDA-type ionotropic transmembrane

receptor for glutamate that mediates fast synaptic transmission

in the central nervous system (CNS).

AMPARs are found in many parts of the brain and are the most

commonly found receptor in the nervous system.

Agonists

• 5-Fluorowillardiine• AMPA• Domoic acid• Quisqualic acid

Antagonists

• CNQX• Ethanol• Kynurenic acid • NBQX • Perampanel• Tezampanel• L-Theanine

AMPA receptorsNMDAreceptor

Na+Na+Na+Na+Ca2+

synapticstrengthening 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 glutam ate because its channel is blocked by Mg . 2+

With high presynaptic activity m ost of the AMPAreceptors 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+

Ca2+ acts as important secondary messenger

activates intracellular cascades.

Ca2+ binds to calmodulin protein which in turn

activates protein kinases like CAM Kinase

CAM KINASE EFFECTS AMPA RECEPTORS IN TWO WAYS-

phosphorylates AMPA receptors already present in dendritic spine membrane

increasing their conductance to sodium ions.

promotes intracellular AMPA receptors to move to the membrane making more receptors available to stimulate the spine.

LONG TERM POTENTIATION

KAINATE RECEPTORS

Physiological studies have been identified both post-and

presynaptic roles for kainate receptors-

- presynaptic kainate receptor facilitate or reduce the neurotransmission depending on where they are in the brain.

- postsynaptic kainate receptors can directly mediate excitatory transmission.

Kainate receptors, or KARs, are ionotropic receptors that

respond to the neurotransmitter glutamate.. KARs are less

understood than AMPA and NMDA receptors.

Antagonists

a. CNQXb. DNQXc. Ethanold. NS102 e. Kynurenic acid f. Tezampanel

Physiological/pathological roles

AMPA receptors mediate most fast EPSPs in the CNS

Kainate receptorsRegulation of neuronal excitability

epilepsy, excitotoxicity and pain

NMDA receptors mediate most fast EPSPs in the CNS

AnaesthesiaLearning and memoryDevelopmental plasticityEpilepsyExcitotoxicity (eg stroke)Schizophrenia

Metabotropic glutamate (mGlu) receptors are G-protein coupled receptors activated by glutamate, the major excitatory neurotransmitter of the CNS.

METABOTROPIC GLUTAMATE RECEPTORS

g

ba

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

• (Gαs, Gαi, Gαq)• GDP bound to a when inactive

GDP

g

ba

G-protein coupled receptors

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.

GDP

GTP

aGTP

g

ba

cAMP pathway

Cell membrane

GDP

GTP

aGTP

• Gαs binds to Adenylate Cyclase (AC) and stimulates cAMP synthesis from ATP

• Gαi binds to AC and inhibits cAMP synthesis

AC

ATP

cAMP

Glutamate Receptors Overview