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| Question | Answer |
| How does the topology and amino acid sequence vary between NMDAR and AMPA/Kainate receptors? | Topology is the same - amino acid sequence different. |
| Where is the Q/R site and what does it determine? | Located on the TM2 loop, determines permeability to Ca2+ |
| What is the structure of the AMPA receptors? What are the constitutional subunits? | Tetrameter - GluA1-4 |
| What is the endogenous agonist which binds to AMPAR and Kainate receptors? | Glutamate |
| What are the subunits which make up a kainate receptor? Which subunits can not form a functional receptor if they are the sole subunit? | GluK1-5 GluK4 and GluK5 can't form a functional receptor on their own >> receptor won't make it to the surface. |
| What shape is the Amino terminal domain in an GluA2 tetramer? And the LBD? | Clam shell (V), same but at 90 degrees to each other (< |
| What is the structure of the transmembrane domain similar to? | Inverted K+ channel pore |
| What type of synaptic transmission do AMPA receptors mediate? | fast |
| Which ions pass through an AMPA receptor? | Na+ in (Ca2+ in sometimes) K+ out |
| Why do GluA2 receptors have relatively low Ca2+ permeability? | Positively charged arginine (R) residue is expressed rather than neutral glutamine (Q) |
| What percentage of GluA2 receptors are edited to express the arginine (R) residue? | 99% |
| What are the molecules on the Q/R site? What effect do they have? | Q - Spermidine, +ve charge, blocks the channel R - Arginine residue, +ve charge inhibits spermidine block |
| What type of current is seen in a GluA2Q/GluK2Q (neutral glutamine at Q/R site). What happens at positive membrane potentials up to 80mV? | 1)Inwardly rectifying - more inward current than outward. 2)Little outward current as channel is blocked on the inside by polyamines - outward current increases around +80mV because large +tive current unblocks channel. |
| What is the current like through GluA2R or GluK2R (R edited +charge at Q/R site)? Why? | Straight line current - no rectification. Charged arginine prevents polyamine (spermidine) from causing a block. |
| Name three endogenous AMPA agonists - which is the partial? | Glutamate AMPA Kainate (partial) |
| What is NBQX? | Competitive AMPAR antagonist |
| What does AMPA cause at at AMPARs? | Fast desnsitisation |
| What is perampanel? | AMPAR negative allosteric modulator |
| What type of drug is Cyclothiazide? What does it do? | 1) Amapkine 2) Positive allosteric modulator - inhibits glutamate-induced fast desnsitisation |
| What are the differences in terms of current/desensitisation induced by Kainate and 5-fluorowillardine (or AMPA)? | Kainate produces small steady current with no desensitisation. F-W or AMPA produce large peak current which rapidly desensitises. |
| Explain the structure of the ligand binding zone (S1S2) in terms of dimers. | S1 and S2 are both made up of a set of D1 and D2. D1 sits on top of D2. The two pairs face each other so D1 faces D1 and D2 faces D2. |
| Through which part of the dimer that makes up S1 and S2 is the majority of the dimer assembled? | D1 |
| What happens when glutamate binds in between D1 and D2? | D2 moves up towards D1, causing the linkers holding D2 to the membrane to open outwards in scissor like motion allowing the pore to open. |
| How does desensitisation occur regarding the dimer? | The dimer undergoes a conformational change causing the bonds between D1 to change. A rotation of one of the paris of the subunits around the axis relieves the strain on the linkers causing the pore to close. |
| Which is more potent: LY404187 or cyclothiazedine? | LY404187 |
| How do positive allosteric modulators (AMPAKINES) enhance the effect of agonists? | Block desensitisation of AMPARs. |
| Where do ampakines bind? What effect does this have? | LBD interface - Between D1 units of the dimer. Stabilises reactions between D1 regions and prevents the conformational change which leads to desensitisation. |
| What affect do ampakines have on NMDARs? | Increase recruitment of NMDARs by increasing current through AMPARs (because that removes the Mg2+ block) |
| What other effect does increased current through AMPARs have? | Leads to greater depolarisation of membrane which can activate voltage-dependent calcium channels. |
| What are the potential therapeutic uses of ampakines? What is this based on? | 1) Improve cognitive impairment caused by neurodegenerative diseases (parkinson's, alzheimer's), schizophrenia and sleep deprivation 2) Ampakines facilitate LTP. Showed improvement in animal models of learning and memory. |
| Where is it thought that NAMs bind to AMPARs? How do they work? | Bind between TM1 and TM4 adjacent to the peptide linker which connect the Transmembrane region to the ligand binding region. 'Clamps' the ion channel shut. |
| What is a therapeutic use of perampanel? | anti-convulsant - treatment for partial seizures. |
| Where are Kainate receptors expresses? (3) (GluK1?) | 1)Dorsal root fibres 2) GluK1 expressed in C nociceptive fibres (involved in pain transmission) 3) Hippocampus |
| What type of transmission are kainate receptors involved in in the hippocampus? | High frequency |
| What ions are kainate receptors permeable to and what does this depend on? | Na+ in, Ca2+ in (depending on Q/R editing state), K+ out. |
| Where are kainate receptors located in the hippocampus? | pre synaptically on CA3 mossy fibres |
| What does activation of the kainate receptors in the CA3 mossy fibres lead to? (2) | 1) Increased glutamate release 2) Induction of NMDAR independent LTP synaptic transmission |
| What effect does kainate have at kainate receptors? | Agonist - desensitizing. |
| What is Domoate? What effect does it have at AMPAR? | Domoate is a desensitizing agonist at kainate receptors. At AMPAR it is a partial agonist with no desensitising effect. |
| What are CNQX and ACET? How do they differ in terms of selectivity? | Competitive antagonists at kainate receptor. ACET is selective for GluK1 subunit. CNQX is also an competitive antagonist at NMDAR and AMPAR. |
| Where can Kainate be extracted from and what can it be used for? | Red algae and anthelmintic (expels worms) |
| What does lectin concanavalin A (con A) do? What is it? | Blocks kainate induced desensitization. Plant |
| How has it been shown in CA3 mossy fibres that KAR are responsible for LTP? | D-AP5 (NMDAR antag.) didn't block LTP ACET (Gluk1 antag) blocked LTP |
| How might the KAR (Gluk1) be involved in glut release and why is this a positive feedback loop? | Calcium permeable > Influx calcium leads to glutamate release> Increased glutamate leads to further activation of KAR > More calcium current more glutamate release and so on. |
| What might the Ca2+ induced release of glutamate via KAR underly? | Long-term synaptic potentiation of synaptic transmission in the MF-CA3 pathway. |
| What are the 3 potential therapeutic uses of Kainate receptor antagonists? | 1) Epilepsy 2) Neuropathic pain 3) Migraines |
| How might KAR antagonists work to prevent epilepsy? | Prevent epileptogenesis. Blocks convulsions in animal models of epilepsy. |
| How might KAR antagonists work in neuropathic pain? | GluK1 is expressed in C nociceptive fibres - block them with antagonist to prevent transmission. |
| How might KAR antagonists work to treat migraines? | Gluk1 receptors present on trigeminal neurons (major part of pathway). Antagonists block pain responses in animal models of migraine. |
| What is sumatriptan? What does it treat? | 5-HT agonist, reduces vascular inflammation associated with migraine. |
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