Glutamatergic Signalling Flashcards
How can glutamate donate protons ?
From both carboxyl groups
What effect does glutamate have?
Excitatory
What are some non-neuronal roles of glutamatergic signalling?
bone, testis, pancreas, hormonal system and gut
What is EAAT?
Transporter for recycling glutamate through glial cells
Where are EAAT1-5 located?
o EAAT1 and 2 – astrocytes and microglia
o EAAT3 – cerebral neurons
o EAAT4 – cerebellar neurons
o EAAT5 retinal
Describe the synthesis and recycling of glutamate
- Takes place in CNS as glutamate cant cross the BBB
- Derived from glutamine
- Normally made in astrocytes
- Recycled back to glial cells to turn back into glutamine before being synthesised back to glutamate in a cycle
Which ion does ionotropic signalling of glutamate allow influx of?
Ca2+
What are the receptor agonists for glutamate receptors?
NMDA – requires glycine as a co-agonist, calcium flux related to synaptic plasticity important in learning and memory
o AMPA - plasticity and synaptic transmission, particularly LTP
o Kainate – both pre-synaptic and post synaptic, synaptic plasticity
o Non-selective cation channels: Na+ and K+
Describe the action of metabotropic glu receptors
- Glu binds to receptor
- Causes conformational change
- Causes alteration to post synaptic molecules – 2nd messengers cause change in metabolism within cell
- Can cause apoptosis, movement of Ca2+ molecules, gene transcription
How can you distinguish between different ionotropic glu receptors?
agonist dependency
What occurs on the post- synaptic membrane?
receptor clustering
What types of proteins are involved in formation of the postsynaptic scaffold?
membrane bound
cytoskeletal
scaffolding
modulatory
What is glutamate homeostasis regulataed by? What is the IC level of glu compared to EC?
- IC level is 1m times that of EC level
* Regulated by sodium dependent glutamate transporters mainly on the astrocytes
What are some of the mechanisms for calcium regulation?
o Ca2+ ATPase – efflux o Na/Ca2+ exchanger – efflux o Ca2+ sequestration by ER o Ca2+ sequestration by mitochondria o IC Ca2+ buffering by Ca2+ binding proteins
What are the concs of IC and EC Ca2+?
- IC Ca2+ is 100nM (if you include bound cytosolic its 1mM)
* EC Ca2+ is 1uM
What is glutamate excitotoxicity implicated in?
• Implicated in ischaemia, trauma, hypoglycaemia, hypoxia, seizures, AD, PD, Huntington’s and ALS
What can GluR overactivation lead to?
Ca2+ overload Cell death via: o Membrane breakdown o Cyctoskeletal alterations o NO-derived free radicals – leads to peroxynitrite generation which damages cells
What are they two hypotheses for the relationship between Ca2+ influx and neurotoxicity? What is evidence?
• Debates whether linear relationship between Ca2+ influx and neurotoxicity (Ca2+ load hypothesis) or distinct Ca2+ signalling pathways are related to influx and therefore neurotoxicity (source specific hypothesis)
o Evidence for SSH – distinct influx pathways determine vulnerability
What is the structure of AMPA receptors ?
• Consist of 4 potential subunits in a heterotetrameric structure
What is the basis of excitotoxicity in Parkinson’s?
- Normally balance between striatal activatation through NMDA receptors and inhibition through D2 receptors
- Depletion of dopamine results in glutamatergic overactivity and change in NMDDA subunits (NR1, NR2B decrease and NR2A unchanged)
- There PD is a secondary glutamate overactivity syndrome
What is the treatment for glutamate overactivation in Parkinsons in animal models?
o Many non-selective NMDA antagonists tried in animals
o Show reduction in Parkinsonian findings
o Not well tolerated in primates due to hallucinations and sedation
How is glutamate excitotoxicity thought to be involved in AD?
- Glutamate may be a major executor of neuronal damage in AD
- Amyloid beta and tau are related to glutamate
- Activation of NMDA receptors enhances production of these factors
What treatment mechanisms are involved in the treatment for AD glutamate excitotoxicity?
• Treatment:
o NMDA antagonist, memantine, has been approved for AD treatment
o An uncompetitive antagonist with improved voltage dependent kinetics and affinity, leads to functional improvement in AD and well tolerated
Is there evidence for glu excitotoxicity in Huntington’s?
- Indirect evidence
- Injections of kainite into rat striatum killed striatal neurons, required glutamatergic afferents
- Agonist for NMDA receptors can reproduce some HD behavioural features in rats
