Lecture 2 - Glutamate Flashcards
What are the 5 core components of a neurotransmitter?
- It is synthesised by enzymes
- Transporters move it into cells
- Transporters move it into vesicles
- It activates receptors
- Molecules terminate their action
How do the 5 core components relate to glutamate?
- Endogenous synthesis via many routes (non-essential amino acid)
- Mainly EAAT2
- VGLUT1-3
- AMPA, NMDA, Kainate, mGluR
What triggers vesicle exocytosis?
Calcium influx
How is glutamate in the synaptic cleft re-uptaken?
Transported into astrocytes by EAAT1/2
Broken down into glutamine by glutamine synthase
Glutamine pumped into extracellular space by glutamine transporter
Glutamine uptaken by presynaptic membrane
Converted back into glutamate by glutaminase
Describe the general structure of an ionotropic glutamate receptor
Tetramer (4 subunits) Extracellular N terminus Intracellular C terminus 3 transmembrane domains 1 partly transmembrane domain that forms the pore
What subunits make up the
- AMPA receptor
- NMDA receptor
- Kainate receptor
AMPA = GluA1-4 NMDA = GluN1-3 Kainate = GluK1-5
What determines the permeability of an AMPA receptor to Calcium?
The GluA2 subunit has a site in the amino acid chain that can be Q (glutamine) or R (arginine). Glutamine allows permeability to calcium. Arginine makes it impermeable.
Which ions are the following receptors permeable to?
- AMPA receptor
- NMDA receptor
- Kainate receptor
AMPA = Na+, K+, sometimes Ca2+ NMDA = Mainly Ca2+, also Na+ Kainate = Na+ and K+
What specific kind of structure does the NMDA receptor have?
Heterotetramer - must have two GluN1 subunits and two GluN2 subunits
What 3 things are required for NMDA receptor activation?
- Agonist binds to main receptor site
- Glycine or D-serine binds to modulatory site
- The Mg2+ block is removed by depolarisation mediated by Na+ influx through AMPA receptors
Which neurotransmitters are the ‘fast’ neurotransmitters (act through ionotropic receptors)?
Glutamate, GABA, Glycine, (amino acids)
Ach, 5-HT, (biogenic amines)
ATP
What are the 3 groups of mGluRs and what G protein are they coupled to?
Group 1: mGlu1, mGlu5, Gq
Group 2: mGlu2, mGlu3, Gi/o
Group 3: mGlu4, mGlu6-8, Gi/o
What is the location and function of each mGluR group?
Group 1: Postsynaptic, slow excitatory, increases intracellular calcium
Group 2 + 3: Presynaptic, inhibitory
Name an agonist, antagonist and positive allosteric modulator of the AMPA receptor
Agonists: AMPA, Glutamate
Antagonists: NBQX, Telampanel
PAM: Cyclothiazide, Ampakines
Name an agonist and antagonist of the NMDA receptor
Agonists: NMDA, Glutamate, Aspartate
Antagonists: AP5
Name an agonist and antagonist of the Kainate receptor
Agonists: Kainate, Glutamate, Demoic acid
Antagonists: CNQX, ACET
What is the location and function of each ionotropic glutamate receptor?
AMPA: Postsynaptic, fast excitatory
NMDA: Postsynaptic and presynaptic, slow excitatory (LTP/synaptic plasticity, excitotoxicity)
Kainate: Postsynaptic excitatory, presynaptic inhibition
How many genes are there for the GluN1 and GluN2 subunits?
GluN1 = single gene with 8 splice forms GluN2 = 4 different genes
On which subunits of the NMDA receptor is the agonist binding site, modulatory site and allosteric site located?
GluN2 = Agonist binding site GluN1 = Modulatory site, Allosteric site
What are the effects of ketamine?
Medication causing anaesthesia, pain relief, sedation and memory loss
How does ketamine work?
Selective antagonist of the NMDA receptor
