Glutamatergic Transmission Flashcards
Name the neurotransmitters involved in amino acid neurotransmitter systems.
Glutamate.
Glycine.
GABA.
Briefly describe the two ways glutamate is synthesised.
- Glutamic acid, or glutamate, is synthesised during an intermediate step in the citric acid cycle by mitochondrial glutamate dehydrogenase.
- Glutamate is synthesised from glutamine by glutaminase in the CNS.
What are the three types of ionotropic glutamate receptors?
AMPA.
Kainate.
NMDA.
What are the subunits of AMPARs?
GluA1-4.
What are the subunits of kainate receptors?
GluK1-5.
What are the subtypes of NMDARs?
GluN1.
GluN2A-D.
GluN3A-B.
What are the three types of metabotropic glutamate receptors?
Group I-III.
What are the subtypes of Group I mGluRs?
mGluR1.
mGluR5.
What are the subtypes of Group II mGluRs?
mGluR2.
mGluR3.
What are the subtypes of Group III mGluRs?
mGluR4.
mGluR6.
mGluR7.
mGluR8.
When are AMPARs permeable to calcium ions?
When no GluA2 subunit is present.
What does activation of AMPARs produce?
EPSPs.
What is the role of an AMPAR?
Mediate fast excitatory neurotransmission.
Name some AMPAR agonists.
Glutamate.
AMPA.
Kainic acid.
Name some AMPAR antagonists.
CNQX.
NBQX.
What are the two primary structures of AMPARs?
Heteromeric GluA1/GluA2.
Heteromeric GluA2/GluA3.
What structure of AMPAR is usually present in small fractions?
Homomeric GluA1.
What do TARPs bind to in order to mediate postsynaptic localisation?
PSD-95.
What is palmitoylation?
Lipid modification that occurs by post-translational addition of a long-chain fatty acid to a cysteine residue.
What is the purpose of palmitoylation?
To regulate AMPA receptor trafficking.
What does TARPs stand for?
Transmembrane AMPAR regulatory proteins.
Why do TARPs associate with AMPARs?
To allow AMPARs to interact with various scaffolding proteins found in the postsynaptic density.
Name the three main scaffolding proteins found in the PSD.
PSD95.
PSD93.
SAP102.
What is the function of cell adhesion molecules?
To structurally and functionally stabilise the pre- and postsynaptic sides of the synapse.
What are the two main roles of scaffolding proteins at the PSD?
Trafficking and stabilising glutamate receptors at the synapse.
Mediating intracellular signalling stimulated by activation of the receptors.
Why are AMPARs clustered together in the synapse, directly opposite the active zone?
AMPARs have a low affinity for glutamate.
What is the purpose of the C-terminal on an AMPAR?
It is a site that allows for changes in the existing properties of AMPARs that are anchoring in the PSD.
What happens to the regulatory domains of the C-terminal of AMPARs?
They undergo posttranslational modifications, including protein phosphorylation, ubiquitination and palmitoylation.
Where has AMPAR exocytosis been observed?
At synapses.
Perisynaptic to the PSD.
On the dendritic spine.
On the spine shaft.
On the soma.
Which ions does NMDAR conduct?
Sodium.
Potassium.
Calcium.
NMDARs are either di-heteromeric or tri-heteromeric. What does this mean?
Di-heteromeric = up to two types of different subunits.
Tri-heteromeric = three types of different subunits.
What is the conventional structure of an NMDAR?
Two GluN1 subunits and two GluN2 subunits.
NMDARs have an additional co-agonist site for which molecule?
Glycine.
What is the role of the glycine binding site in NMDAR activation?
Occupancy of the glycine site is obligatory for activation of NMDARs.
Which type of molecule enhances NMDAR activation?
Endogenous polyamines, e.g. spermine.
How does zinc inhibit NMDAR action?
It can block both the channel pore and the agonist binding site.
Magnesium ions block NMDARs in a voltage-dependent manner. What does this mean?
At the RMP, the positive of the magnesium ion is attracted to the negative interior of the neuron, so it blocks the channel pore.
Which enzyme converts glutamine to glutamate in the presynaptic terminals of glutamatergic neurons?
Glutaminase.
What happens to glutamate once it has been released from nerve terminals?
It is taken up into glial cells.
What is glutamate converted into when it has been taken up into a glial cell, and by which enzyme?
It is converted into glutamine by glutamine synthetase.
What happens to glutamine when it is pumped out of a glial cell by SN1?
It is taken up by nerve terminals and converted back into glutamate to replenish the transmitter pool.
Name the three glutamate transporters responsible for the uptake of glutamate into glial compartments.
GLT-1.
GLAST.
EAAC1.
How do AMPARs and NMDARs behave when multiple synaptic inputs occur simultaneously compared to a single synaptic input?
Single synaptic input = short-lasting EPSP mediated by AMPARs.
Multiple synaptic inputs = the same single synaptic input generates a longer-lasting EPSP mediated by AMPARs and NMDARs.
How do AMPARs and NMDARs impact current when the membrane potential is close to RMP?
AMPARs conduct a large inward current.
This is not seen in NMDARs.
How do AMPARs and NMDARs impact current when the membrane potential is depolarised above 0mV?
Both AMPARs and NMDARs conduct similar outward currents.
What is the role of NMDARs?
To mediate slower synaptic responses.
What is the unconventional structure of an NMDAR?
It incorporates GluN3 subunits in addition to either GluN1 or GluN2.
Name the 5 conventional NMDARs.
GluN1.
GluN2A-D.
Name the two unconventional NMDARs.
GluN3A and GluN3B.
Name the two channel blockers for NMDARs.
Memantine.
Magnesium ions.
Name the five antagonists for NMDARs.
D-AP5.
5,7-DCKA.
Ifenprodil.
PCP.
Ketamine.
Name the two agonists for NMDARs.
Glutamate.
NMDA.
Name the two co-agonists for NMDARs.
Glycine.
D-serine.
Name the five modulators for NMDARs.
Polyamines.
Zinc ions.
Histamine.
Redox.
Pregnenolone.
The current-voltage (I-V) curve for an NMDAR can be made to resemble one for an AMPAR by doing what to the bathing medium?
Removing magnesium.
What is another term for bathing medium?
Perfusate.
Why are AMPARs localised near to the site of presynaptic release?
They have a low affinity for glutamate.
In adult rodent brains, where is GluN1 expressed?
Throughout the brain.
In adult rodent brains, where is GluN2A expressed?
Hippocampus.
Superficial layers of cortex.
Superficial layers of medial and lateral entorhinal cortex.
Cerebellum.
In adult rodent brains, where is GluN2B expressed?
Hippocampus.
In adult rodent brains, where is GluN2C expressed?
Cerebellum.
NMDARs are coincidence detectors. What does this mean?
NMDARs only pass current when they are stimulated by presynaptically-released glutamate AND when the postsynaptic cell is depolarised by activity at adjacent synapses.
Why is repetitive stimulation required for an NMDAR to pass current?
The depolarisation produced by single inputs is not sufficient to relieve the magnesium blockage of the channel pore.
What indicates the presence of synaptic plasticity?
A persistent increase in the postsynaptic AMPAR-mediated evoked response.
Describe the two ways in which synaptic plasticity is induced.
Intense electrical stimulation of presynaptic inputs.
Pairing presynaptic action potentials with postsynaptic depolarisation.
What is the role of AMPARs in the expression and maintenance of multiple forms of plasticity?
AMPARs are rapidly inserted into or removed from the synapse.
Describe two ways in which protein kinases increase synaptic strength.
Phosphorylate AMPARs at the synapse to change their properties or availability in the reserve pool for insertion at the neuronal surface.
Activate translation factors required for the stabilisation of local mRNAs.
How does local protein synthesis increase synaptic strength?
Provides a feedforward mechanism to persistently increase receptor numbers, receptor trafficking, levels of scaffolding and cytoskeleton proteins, and lateral diffusion and stabilisation of AMPARs.
What impact does NMDAR antagonism have on synaptic plasticity and memory?
Blocks synaptic plasticity.
Impairs memory.
AMPAkines enhance synaptic function. How could they be used clinically?
To improve cognition and treat brain disorders.
What does KARs stand for?
Kainate receptors.
What do AMPARs, NMDARs and KARs have in common structurally?
They are all tetramers.
Name the five different subunits that can make up a KAR.
GluK1-5.
Name the genes that encode the subunits for KARs.
Grik 1-5.
What two types of receptors can the GluK1-3 subunits form?
Homomeric or heteromeric.
How do GluK4-5 subunits differ from GluK1-3 subunits?
GluK4-5 subunits can only participate in functional receptors when associated with any of the GluK1-3 subunits.
Which ions are KARs permeable to?
Sodium.
Potassium.
What type of KARs are also permeable to calcium?
Some canonical KARs.
Where are functional KARs located?
Pre-, post-, and/or extra-synaptic sites.
What are the two roles of functional KARs?
Regulate glutamate release presynaptically.
Modulate postsynaptic transmission and plasticity.
Describe the process of metabotropic signalling by non-canonical KARs.
Non-canonical KARs activate G-proteins.
This stimulates phospholipase C and PKC.
What is the role of metabotropic signalling via non-canonical KARs?
To regulate ion channels and intrinsic excitability.
Are canonical KARs ionotropic or metabotropic?
Ionotropic.
Are non-canonical KARs ionotropic or metabotropic?
Metabotropic.
Which two receptors generate synaptic responses with a remarkably similar onset and decay time course?
NMDARs and KARs.
How do KARs regulate glutamate release?
By modulating VGCC activity in the presynaptic membrane.
What impact do calcium permeable KARs have on glutamate release and how?
They enhance glutamate release via increased calcium ion transients and further depolarisation of the terminal.
What impact does weak KAR activation have on the postsynaptic membrane?
Inserts AMPARs and KARs into the membrane.
What impact does strong activation of KARs have on the postsynaptic membrane?
Internalises AMPARs and KARs.
What type of receptors are mGluRs?
G-protein coupled receptors (GPCRs).
Describe the structure of mGluRs.
Consist of 7 transmembrane spanning regions.
What role do mGluRs play in neurotransmission?
Slow modulatory role.
Where are Group I mGluRs located?
Postsynaptically.
Where are Group II and Group III mGluRs located?
Presynaptically.
What are the four functions of Group I mGluRs?
Produce slow depolarisation.
Release calcium ions from intracellular stores.
Promote release of glutamate or GABA.
Regulate plasticity.
What are the two functions of Group II and Group III mGluRs?
Produce inhibition of AP-evoked glutamate release.
Inhibit release of glutamate or GABA.
Which type of G-protein do Group I mGluRs couple to, and what does this lead to?
Couple to Gq.
Leads to an increase in IP3 and DAG.
Which type of G-protein do Group II and Group III mGluRs couple to, and what does this lead to?
Couple to Gi.
Leads to downregulation of cAMP activity in the postsynaptic cell.
Describe the glutamate hypothesis for schizophrenia.
Impaired glutamatergic signalling and dysfunctional NMDARs are thought to play a role in schizophrenia.
How does PCP psychosis support the idea that dysfunctional NMDARs play a role in schizophrenia?
PCP psychosis is clinically indistinguishable from schizophrenia.
How does ketamine support the idea that dysfunctional NMDARs play a role in schizophrenia?
Ketamine exacerbates psychosis in schizophrenic patients.
The EEG markers for schizophrenia are mimicked by ketamine.
