Excitatory Amino Acids - Glutamate

Anna mph
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Anna mph
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Degree Neuropharmacology Flashcards on Excitatory Amino Acids - Glutamate , created by Anna mph on 12/18/2015.

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Question Answer
What is the principle excitatory amino acid found in all mammalian cells? L-glutamate
What can L-glutamate not cross? Blood brain barrier
Which conditions are associated with a malfunction in glutamate transmission? Epilepsy, schizophrenia, parkinsons and alzheimers
What are the two subtypes of glutamate receptors? Ionotropic and metabotropic
What are the group 1 metabotropic receptors? mGlu1,5
What are the group 2 metabotropic receptors? mGlu2,3,
What are the group 3 metabotropic receptors? mGlu4,6,7,8
What is the glutamate transporter located on the postsynaptic membrane? EAAT3
What are the transporters located on the astrocyte for the up take of glutamate? Which ions are required? EAAT1 and EAAT2 3Na+ and H+ in, K+ out
What substances and which enzyme is required for the conversion of glutamate to glutamine? Glutamine synthetase ATP+NH4
Which transporter transports glutamate from the cytosol into vesicles? VGLUT
What is the most likely transporter located on pre synpatic terminal? EAAT2
Which enzyme converts glutamine to glutamate? Glutanimase
How many subunits are in an NMDA receptor and what are they? 4 2GluN1 and 2GluN2
How many transmembrane domains does each subunit have? 4
Which transmembrane domains make up the ligand binding domain? S1S2
What is S1? Extracellular peptide chain extending from TM1
What is S2? Extracellular peptide chain extending join TM3 and TM4
Which transmembrane chain makes a re-entrant loop forming the pore of the channel? TM2 - loop points in towards channel
Which ions can pass through an NMDA channel? Na+ and Ca2+ flow inwards K+ flows outwards
What are the three important properties of NMDA channels regarding Calcium, glycine and magnesium NMDA channels have a high Ca2+ permeability Mg2+ blocks the pore Glycine is a co-agonist
Which subunit binds the glycine? GluN1
Which subunit binds the glutamate? GluN2
What are the sub categories of GluN2 receptors? GluN2A, GluN2B, GluN2C and GLUN2D
At what membrane potential is the magnesium block removed? ~ -35mV
How does the pore open? Binding of glutamate and glycine causes a conformational change
Which other type of receptor is usually present where NMDAR are found? What is the purpose of this? AMPA Sufficiently depolarise the membrane to remove the Mg2+ block
In terms of neuroplasticity what is the NMDA receptor and why? Coincidence detector Ca2+ entry depends on both the membrane being sufficiently depolarised and glutamate release.
What type of drugs can block an NMDA receptor? Voltage dependent (positively charged)
Explain the shape of a NMDAR - I/V curve Magnesium block is progressively lost (downwards U shape) then at -35mV block is completely removed and current becomes completely voltage dependent.
What is eliprodil? Where does it bind? Which subunit is it selective for? Negative allosteric modulator Site E (interface between GluN1 and GluN2B) GluN2B
What are D-AP5 and D-CPPene? Glutmatergic antagonists - bind at S1S2 on GluN2B
What are Kynuernate and 5-7 dichlorokynurenic acid? Competitive antagonists of glycine - bind at S1S2 site on GluN1
Where do ketamine, memantine, PCP and MK-801 all bind? What does this make them? Binding site C - Use dependent blocks
What does NMDA stand for? N-Methyl-D-Aspartate
Which binds with more affinity, R-AP5 or R-CPPene? R-CPPene
What is an agonist for the glycine binding site? D-Serine
What determines the affinity of Glycine to the Glu1 subunit? The type of GluN2 subunit present
What is D-serine released from? Astrocytes
Where is kynurenate produced from? What more potent drug has been developed from it? Glial cells 5,7-dichlorokynurenate
What is memantine used to treat? What is its affinity like? Memory impairment in moderate/severe alzheimers, vascular dementia and dementia in parkinsons low affinity channel blocker (same for ketamine)
Which are the two high affinity channel blockers? PCP (phencyclidine) and MK-801
How much higher is MK-801 affinity than ketamines? what is its dissociaton rate like? 150-fold much slower dissociation rate
What causes the tonic activation of NMDARs in alzheimer's disease? soluble B-amyloid plaques
How do solid B-amyloid plaques cause tonic activation of NMDARs? Increase of glutamate in synapse by inhibition of glutamate transporters. Also removal of Mg2+ block.
What is the effect of tonic background noise and what effect does this have on normal physiological signals? Background noise - hard to detect normal physiological responses - impaired cognition.
In terms of membrane potentials why is memantine effective? Blocks NMDAR at tonic activation at -50mV but not under physiological conditions when a signal causes a depolarisation of around -20mV. BLOCKS PATHOLOGICAL NOT PHYSIOLOGICAL SIGNAL
Why is MK-801 not useful clinically in terms of membrane potentials? Remains bound to (and blocks) channel in pathological and physiological conditions. Blocks signal transmission.
What effect might memantine have on neurodegeneration? Preventative - may reduce neurodegeneration by preventing neurotoxicity (alzheimer's causes increased synaptic glutamate which would cause increased inward calcium current through over active NMDAR)
What are the 2 main physiological roles of NMDARs? 1) Mediate slow EPSP via Ca2+ and Na+ 2)Synaptic plasticity - change strength of synaptic pathways and consolidate new path ways)
What are the two processes within synaptic plasticity mediated by NMDARs? 1) LTP - long term potentiation of synaptic transmission 2) LTD - Long term depression of synaptic transmission
Which two factors determine whether LTP or LTD are induced? 1) Frequency of stimulation 2) Duration of stimulation
What happens when you stimulate the Schaffer collateral pathway in the hippocampus at 100Hz for 1 sec? Why? LTP - increased amplitude of current, last for hours AMPA receptors inserted into membrane
What happens when you stimulate the schaffer collateral pathway in the hippocampus at 1Hz for 15 mins? Why? 1) LTD - current decreases 2) Down regulation of AMPA receptors at membrane
How can you test that NMDAR are involved in LTD and LTP induction? D-AP5 (NMDAR antagonist) blocks induction.
What are the four main pathophysiological roles of NMDA receptors? 1) Excitotoxicity 2) Epilepsy 3) Transmission of pain responses 4) Schizophrenia
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