OCB03-2008 GLUTAMATE Flashcards
Why is a neuronal output described as an “integrated response”?
Determined by the NUMBER of excitatory and inhibitory synaptic inputs and the STRENGTH of each individual input
How can the timing of neuronal inputs affect the post-synaptic output?
Excitatory inputs close together = summation
Inhibitory inputs can dampen down the excitatory input/depolarisation if they occur simultaneously
What is glutamate and its importance in the nervous system?
Amino acid
Major excitatory neurotransmitter in the CNS
Describe some prominent glutamatergic pathways in the brain.
Cortico-cortical pathways - inflammation processing centres and modulation of neuronal activity
Between thalamus and cortex
Extrapyramidal pathway (cortex and striatum) - regulates involuntary movement
What psychiatric conditions are glutamatergic pathways implicated in? (4)
Depression
Anxiety
Schizophrenia
Drug addiction
What main functions is glutamate involved in? (3)
Memory
Emotion
Cognition
Can glutamate cross the blood-brain barrier?
No
How can glutamate synthesised in the CNS?
Metabolism of glucose (TCA cycle)
From glutamine in astrocytes
What is the concentration of glutamate in neuron cytoplasm?
1mM
What is the concentration of glutamate in presynaptic vesicles?
20-100mM
Describe the process of synaptic transmission in glutamatergic neurons.
AP depolarises neuron causing voltage-gated Ca channels to open = Ca++ influx
Exocytosis of presynaptic glutamate and diffusion across synapse to interact with postsynaptic receptors
Glutamate diffuses out of synaptic cleft and taken up by glutamate transporters on astrocytes
Describe the process of the recycling of glutamate after transmission.
Glutamate taken up into astrocytes by glutamate transporters
Glu –> Gln by glutamine synthase
Gln extruded by glutamine transporters into extracellular space
Gln taken up into neurons by glutamine transporters
Gln –> Glu by glutaminase
What is essential to terminate synaptic transmission via glutamate?
Uptake of Glu by astrocytes via glutamate transporters
What are the two main types of glutamate receptor?
Ionotropic
Metabotropic/7TMGPCR
Describe glutamate ionotropic receptors.
Fast transmission
Na+, K+, Ca+ allowed through (depolarise membrane)
4 sub-units
Post-synaptic
What are the three classes of ionotropic glutamate receptor?
NMDA (N-methyl-D-aspartate) receptors
AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors
Kainate receptors
Where is kainate commonly found in nature?
Seaweed
Which ionotropic glutamate receptors are often co-localised together at synapses?
NMDA and AMPA
What is the main function of metabotropic glutamate receptors?
Modulate excitation and synaptic transmission
Describe the activation of AMPA receptors.
Rapid activation and rapid decay ~1-2ms
Usually Na+ depolarisation
Describe the activation of kainate receptors.
Rapid activation and rapid decay ~1-2ms
Usually Na+ depolarisation
Describe the activation of NMDA receptors.
Slower onset and slower decay of several hundred ms
High affinity Glu binding
Na+ and Ca++ influx
What is the Kd of NMDA receptors for glutamate?
5nM
What is the importance of Ca++ influx in NMDA receptor activation?
Modulates activity of Ca-dependent kinases and phosphatases involved in longer term changes in neuronal behaviours
Eg gene expression, learning and memory
What would a block in AMPA or kainate receptors likely cause?
Major inhibitory effects on CNS
What would a block in NMDA receptors likely cause?
Effects on behaviour and memory
Describe the full EPSP in excitatory glutamatergic transmission.
Fast onset due to AMPA or kainate receptors
Long duration due to NMDA receptors
Why do NMDA receptors have a slow onset and slow decay?
Blocked by extracellular Mg++ ions at normal/low membrane potentials
The activity of which glutamate receptors are likely to represent the glutamate concentration in the synapse and why?
AMPA (and kainate) receptors
Low glutamate affinity so bind only in high concentrations and dissociate rapidly
What is the Kd of AMPA receptors for glutamate?
200nM
How many metabotropic glutamate receptors are there?
8
What is the function of presynaptic mGluR?
Inhibit voltage-gated Ca channels = decreased Ca++ influx
Less neurotransmitter release of other neurons or itself
What G protein are mGluRs coupled to?
Gi (inhibitory)
What are the functions of the G protein coupled to mGluRs?
α-GTP = inhibit adenylyl cyclase
βγ:
Reduce activity of voltage-gated Ca channels
Reduce exocytosis presynaptically
Slow hyperpolarisation postsynaptically via K channels
Describe how glutamate excitotoxicity/ischaemic cell death occurs.
Ischaemia = dramatic decrease in ATP production
ATPase pumps stop working = membrane potential depolarises so glutamate transporters stop working
Increased extracellular glutamate
NMDA receptors activated resulting in massive Ca++ influx
Neuronal Ca++ buffering/extrusion capacity overcome
Activation of degradative biochemical processes (eg Calpain)
Cell death in mins
