Glutamate Receptors Flashcards
What are the three main subtypes of ionotropic glutamate receptor?
1) AMPA,
2) kainate (KAR)
3) NMDA receptors
These are determined by distinct gene families.
Describe the relationship between ionotropic glutamate receptor structure & function.
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how do synaptic AMPA & NMDA receptors act in a coordinated manner to mediate neuronal excitation?
1) Neurally released glutamate activates synaptic AMPA receptors
2) glutamate also binds to NMDA receptors but the channel does not initially conduct due to ion channel blockade by Mg2+.
3) The activation of AMPA receptors causes Na influx, causeing a depolarisation of the spine.
4) As a result of the depolarisation, Mg2+ is unblocked from NMDA receptor, (as voltage changes) and calcium can low into cell.
5) This process means the synaptic depolarisation is SLOW.
What is long term potentiation (LTP)
Involving “activity-dependent” changes in synaptic excitatory transmission mediated by glutamate receptors; (synaptic plasticity)
Linked to learning and memory; the hypocamus part of a brain.
On recording the EPSP of this part, high frequency bursts at which the brain LEARNS at occurs but is then MAINTAINED at the elevated new level (does not drop back) It is long term as frequency is remembered.
NMDA has been linked to neurodegeneration (after a stroke)
Can be combated by cognitive enhancing drugs (AMPA-kines)
How are glutamate receptors different ion channels?
It only consist of 4 subunits.
What substrate would block the receptor NMDAR?
The NMDAR conducts
Na+, Ca2+,& K+ but is
blocked by Mg2+
This block is VOLTAGE- DEPENDANT; so at -60mV ions block channel; above this voltage no matter the concentration of Mg, it will not act as a blocker.
Mg blocks channel when Na enters cell, it doesn’t block cell when potassium ions are leaving cell; (allows cell to become positive via the influx of Na)
The drugs Phencyclidine (PCP) and Ketamine also act as voltage blockers
How is NMDA receptors activated? How is this shown?
receptors requires the binding of two different agonists AT THE SAME TIME: glutamate and its co-agonist glycine (or D-serine) to open channel.
There are 2 specific binding sites for Glutamate on the GluN2 SUNUNIT
and 2 binding sites for glycine on the GluN1 SUNUNIT
Shown through whole-cell patch clamp: where inward current (shows channel has opened/receptor activated) is only seen when glycine is present
What are examples of NMDA blockers?
It Conducts Ca2+ and is blocked by Mg2+
Competitively Blocked by APV
Blocked by “channel blockers” MK801, ketamine & PCP.
How are EPSC generated?
glutamate activates cation conducting AMPA receptors to open, which depolarise the cell and cause an EPSC (EPP equivalent)
What part of the NMDA is blocker Mg said to effect?
When Mg is absent, there is a slow EPSC.
With No Mg, the slow component of the receptor is inhibited by blocker APV giving a fast EPSC
but the other blocker CNQX only affects the fast AMPA component and the EPSC remains slow.
When Mg is present, the EPSC is fast even when subject to the same APV blocker; the blocker no shows no efect in making it slow.
APV blocks NMDA receptor
CNQX blocks AMPA receptor which is effected by the blocked state of NMDA.
Mg2+ blocks the slow (NMDA) component of EPSCs and AMPA is mediated by NMDA to control excitability.
Give some examples of the type of NOMENCLATURE used to describe glutamate receptors.
NMDA: GluN1, GluN2A
AMPA: GluA1, GluA2
Kainate: GluK1, GluK2
Describe the structure of he AMPA receptor.
4 subunits: TM1-TMIV (Alpha 1-4) with various binding domains to fulfill its function of FAST SYNAPTIC TRANSMISSION,
The majority of AMPARs are heteromers containing the GluA2 subunit.
majority of GluA2 subunits are RNA edited resulting in the mature protein with an arginine (R) residue in the re-entrant M2 loop instead of the orginal Glutamine (Q) residue.
Why are GluA2 subunits important in AMA receptor function?
enables:
1) Ca2+ permeability
2) single channel conductance, 3) block by endogenous
polyamines.
If this subunit is mutated, receptor function changes significantly.
What is the difference between the two RNA EDITED GluA2 subunits?
The GluA2607Q is Ca2+ permeable (CAN TRANSPORT CALCIUM) & blocked by internal polyamines.
Mature: GluA2607R is Ca2+ impermeable, is insensitive to
internal polyamines and has a reduced single channel conductance of sodium too
This residue site on the M2 loop regulates calcium permebility.
What effect does the drug cyclothiazide have on the AMPA receptor?
It is an AMPA- kine that reduces desensitisation and results in ENHANCED COGNITION.