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| Questão | Responda |
| 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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