Name the 3 types of ionotropic glutamate receptor channels?
AMPA KA NMDA
Name the 4 agonist of ionotropic glutamate receptor?
Glutamic acid AMPA KA NMDA
What is the role of magnesium for the NMDA receptor?
Voltage and use dependant blocker of the NMDA receptor associated ion channel. Moves into the receptor and blocks it
What does the NMDA receptor conduct?
Sodium, calcium and potassium
Name the two types of blockers on the NMDA receptor?
Phencyclidine (PCP) and ketamine act as blockers
What kind of block is produced my the magnesium of the NMDA receptor?
Produces a voltage-dependent block
Under what conditions does the magnesium come in to block the cell?
Where there is a net flow of inward calcium and sodium entering the cell. This is when magnesium enters and blocks the channel
Under what conditions does the magnesium not enter the cell?
When there is a net flow of outward potassium ions leaving the cell. Thus, magnesium does not enter and block the channel.
What subunit does the glutamate bind to?
On the GluN2 subunit.
What subunit does the glycine co-agonist bind to?
Binds to the GluN1 subunit.
What needs to be co-administrated with NMDA to cause the inward current?
Co-administration of glycine
In the absence of glycine how does glutamate still induce a current?
Due to the activation of AMPA receptors But when glycine is present the current is greatly increased because NMDAs are also activated.
Name the co-agonist of the NMDA receptor?
Glycine or D-serine
Name the 2 blockers of the NMDA receptor?
Blocked by APV and by the channel blockers (MK801, ketamine and PCP)
What is the two roles the NMDA receptor play in the body?
Implicated in long term potentiation (LTP) and consequently cognition. Implicated in neurodegeneration that occurs after brain ischaemia "stroke"
What does the NMDA receptor conduct?
Define the term "EPSC"?
Excitatory post-synaptic current
Describe the process of activation of AMPA receptors at excitatory dendritic spines?
1. AP generates the opening of sodium channels. 2. Depolarisation opens calcium channels. 3. Calcium binds to synaptotagmin causing opening of fusion pore. 4. Glutamate passes through fusion pore and diffuses into the cleft. 5. Opening of AMPA by the glutamate-generates EPSC.
Describe the excitatory synapse that is caused by the interplay between AMPA and NMDA receptors?
1. Neurally released glutamate activates synaptic AMPA receptors. Glutamate also binds to the NMDA receptors but do not initially conduct due to the blockage of Magnesium. 2. The sodium influx caused by activation of AMPA receptors causes a depolarisation of the spine. Resulting in the magnesium to unblock the NMDA. Thus, slow synaptic depolarisation. 3. High freq of presynaptic activity will favour NMDA receptor activation.
What part of the EPSC response does the magnesium block?
The slow (NMDA) component
Name the 3 receptors in the ionotropic glutamate receptors?
1. NMDA receptors 2. AMPA receptors. 3. Kainate receptors.
Name the 7 NMDA receptors?
GluN1 GluN2A/B/C/D GluN1/B
Name the 4 AMPA receptors?
Name the 5 Kainate receptors?
Describe the AMPA receptor subunit?
4 TM domains. Ligand binding site on the extracellular side.
What does AMPA receptors mediate?
Fast synaptic transmission in the CNS
What are the AMPA receptors composed of?
Glu A1-4 subunits
Describe the majority of AMPAs ?
Heteromers containing GluA2 subunit
Why is GluA2 so important ?
Critical in determining receptor function including calcium permeability, single channel conductance and block by endogenous polyamines.
How are GluA2 subunits made?
RNA edited resulting in the mature protein containing arginine residue in the M2 loop.
AMPA receptor desensitisation is reduced by?
AMPA-kines such as cyclothiazide.
Why are AMPA-kines important?
Increases sensitivity of the AMPA receptor. Important as appears to enhance cognition.
Define the function of the adenosine deamination?
Adenosine to ionosine editing
What does the M2 Q/R site regulate?
Role of spermine?
Acts as an intracellular AMPA receptor ion channel antagonist. Block the outward current carried by cations.
Describe the model of an ionotropic glutamate receptor subunit? and name the 4 domains?
Amino terminal domain. (ATD) Carboxy terminal domain (CTD) Transmembrane domains (M1-4) Ligand binding domain (S1-2)
When can the AMPA and KA receptors go into the desensitisation state?
Resting Open Densensitised.
Define "flip/flop" region of the AMPA receptor?
Flop desensitised faster than flip. They are generated by alternative splicing.
Describe the structure of the NMDA receptor?
4 transmembrane domains. Ligand gated on the extracellular domain.
What subunits are the NMDA receptors composed of?
GluN1 & GluN2 or NR1 & NR3 subunits.
What are the NMDA receptors subunits similar to in topology?
To the AMPA and kainate subunits.
The role of the NR1 subunit?
The role of the GluN2 subunit?
What site on the NMDAs does the magnesium block?
The asparagine residue on the Q/R site
Describe the 8 stages of brain ischemia (eg. stroke)?
1. Depletion of glucose, glycogen and creatine phosphate. 2. Failure of ion pumps. 3. Membrane potential rundown. 4. AP firing. 5. Glutamate release. 6. AMPA and NMDA receptor activation- excessive calcium influx. 7. Activation of proteases, lipases etc. 8. Neuronal cell death.
How would you treat brain ischemia?
Potential treatment with agonist dependant channel blockers eg. PCP, ketamine.
What are the negative effects of using PCP as treatment of brain ischemia?
Associated with psychotic-like symptoms.
What is long term potentiation a correlation of?
Learning and memory
Name a developmental cognitive enhancing drug?
Describe the 3 stages of Long term potentiation?
1. Increase in glutamate release-> NMDA activation-> calcium influx. 2. Induction: increase in AMPA (gluA1) receptor in the excitatory synapse. 3. Stabilisation: calcium permeation by replacing glua1 receptor with glua1/glua2.
Describe huntington's disease?
Is an incurable neurodegenerative disease.
What are the characteristics of huntington's disease?
By motor dysfunction however cognitive deficits often precede the appearance of the motor problems.
What is the cause of Huntington's disease?
Caused by CAG repeats of the huntington gene.
What can be used to increase LTP and cognition in huntington sufferers?