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38 Cards in this Set
- Front
- Back
What are the two main nt in the brain? |
Glutamate - excitatory GABA - inhibitory |
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What are the different types of glutamate receptors? |
Ionotropic Metabotropic |
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Explain Glutamate Ionotropic receptors When are they activated? What do they allow the flow of? What is the effect of activation? Advantages? |
ligand-gatednonselective cation channel pores, activated when glutamate binds receptor. Allowflow of K, Na and Ca2+. Agonist stimulates EPSC, triggers AP ifenough receptors are activated. Fast inrelaying info. |
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Explain group I glutamate metabotropic receptor |
Stimulation causes PLC to hydrolyse phospholipids in plasma membrane to form IP3 and DAG.
IP3 - hypophilic, travels to ER, opens Ca channels. DAG remains in membrane - cofactor for activation of PKC. Receptors are associated with Na/K channels. Can increase IPSPs |
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Explain Glutamate Metabotropicreceptors |
Indirectly activate ion channels throughsignalling cascade – G proteins. More prolonged stimulus. Excitatorypostsynaptic current. EC region – binds glutamate, phosphorylation ofintracellular region. |
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Where are glutamate receptors present? |
Dendritesof postsynaptic cells and astrocytes (glial cells) and Oligodendrocyte |
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Are the receptors specific to glutamate? |
· Usually not specific – may require another agonist. |
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Explain the Glutamate-gluatamine cycle? |
Ensures adequate supply of glutamate in CNS. Neurones not able to synthesise glutamate and GABA from glucose. Metabolic cycle, release of GABA and glutamate from neurones which are taken up by astrocytes. In return, astrocytes release glutamine (non-neuroactive species)to be taken up by neurones for use as precursor to synthesise glutamate/GABA using glutamine synthetase pathway |
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What type of receptor is the NMDA? |
· Ionotropic. |
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Which ion binds to the NMDA receptor? |
· Internal binding site for an Mg2+ ion At hyperpolarised membrane potentials, this ion blocks the channel - voltage-dependent block Thus, the channel pass cations only during depolarisation. Co-agonist glycine required for opening. |
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Explain the requirements for activation of the receptor |
· So, rely on EPP produced by AMPA to open – not instantaneous.
Requires co-activation by two ligands – glutamate and D-serine/glycine. |
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Which ion causes LTP and LTD? |
· Permeable to Ca2+ -causes LTP and LTDby transducing signalling cascades and regulating gene expression.
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What is another glutamate receptor?
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ionotropic |
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What is LTP? |
repeated stimulationleads to enhanced stimulation |
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Explain the process of LTP |
· Removal of Mg block of NMDA channel bydepolarisation · Sustained glutamate release · Activation of NMDA receptors · Ca entry · Activation of metabolic pathways - binds to calmodulin · Protein phosphorylation · Synthesis of NO - released from presynaptic terminal via retrograde signals · Activation of CREB |
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What is Excitotoxicity caused by? |
· Overstimulation – neurodegeneration and neuronaldamage, specifically NMDA receptors – causes high levels of Ca2+ toinflux into postsynaptic cell. |
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Glutamate and Stroke |
Interruptionof blood supply to the brain. Cell death (necrosis) in the core Excessiveglutamate release in penumbra Sustainedactivation of glutamate receptors Excitotoxicity –uncontrolled entry of Ca2+ andNa+ Cascadeof toxic metabolic events triggered by high [Ca2+] |
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What does high Ca result in? |
Activates cascade of cell degradation – involves proteases, lipases, NO synthase – damagecell structures. Ingestion of excitotoxins (NMDA) – induce excitotoxicity – positionfeedback cell death. |
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What diseases is excitotoxicity invovled in? |
Strokes, NDG disease, MS, Parkinson’s.
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How are receptors changed in synaptic plasticity? |
· Change in number of ionotropic receptors (addedby exocytosis and removed by endocytosis) leads to LTP in hippocampus andneocortex. · Metabotropic glutamate receptors may modulatesynaptic plasticity by regulating postsynaptic protein synthesis through secondmessenger systems. |
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What are other effects of synaptic plasticity? |
· Enhanced transmitter release · Increased sensitivity · Increased protein synthesis |
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Name a drug acting on glutamate receptors |
· MK-801 – NMDA receptor antagonist which blocksexcitotoxicity. But induces psychotic episodes. |
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What is the GABA receptor? |
· Inhibitory (main, 20% – brain), regulates muscletone. Synthesis: metabolite of glutamate or by amination of a-ketoglutaric acid(from TCA cycle) |
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What are GABA drugs? |
· GABA-enhancing drugs are sedative, anaesthetic,anticonvulsant |
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What are the different GABA receptors? |
A, B and C |
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Explain the structure of GABA-A receptor
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ionotropic; pentameric; members of Cys loop family of receptors (inc.glycine, 5-HT). 16 different subunits. Ligand-gated Cl channels. Cl entryhyperpolarises membrane (-65mV)- IPSP. Primarily post-synaptic |
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Explain the structure of GABA-C receptor Which drugs are the receptors insensitive to? |
ionotropic; primarily retinal; r-subunits. Insensitiveto benzo/barbits. |
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Explain the structure of GABA-B receptor |
Metabotropic effects; excitatory Presynaptic and postsynaptic - Stimulate K+ entry - hyperpolarise neurone, prevents Na opening. - Reduce adenylyl cyclase activity and decrease cell's conductance to Ca Slow response. |
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What are GABA-A Receptor Modulators and what are the effects? |
Benzodiazepines- Anxiolytic, hypnotic, anticonvulsant. · |
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how does Benzodiazepines work?
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Potentiates GABA responses by increasingfrequency of Cl channel opening – agonists. · Bind with high affinity to an accessory site onGABA-A receptor · E.g. diazepam long duration of action 24-48 hrs– muscle relaxant. |
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What are issues with Benzodiazepines? |
· Problems of tolerance and dependence · Can cause anterograde and retrograde amnesia
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What is Benzodiazepines a safer alternative to? |
Barbiturates due to higher therapeutic ratio. |
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What are Barbiturates? |
sedatives. Potentiate GABA responses by prolonging Cl channel opening. But can openchannel without GABA – so no longer used therapeutically. |
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Explain the GABA-B receptor |
· gamma-subunit required for benzodiazepine activity · Different isoforms of subunits – combine to give different receptors |
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Explain the GABA-A receptor |
· Activation – fast IPSP. · Increase in Cl- conductance · Studies – gene knockout, ablation of receptorsubunits - alpha1-point-mutated micediazepam-induced sedation and anticonvulsant effects were attenuated but othereffects were unaffected. |
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What is the GABA-glutamine cycle? |
Glutamine is taken up by neurones and converted to glutamate, which is metabolised into GABA - glutamate decarboxylase. Upon release, GABA is taken up into astrocytes and then catabolized into succinate. Glutamine is synthesized from succinate via the TCA cycle |
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Does a low stimulus activate AMPA or NMDA receptors? |
AMPA only as NMDA receptors are blocked by Mg |
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How can NMDA receptors be activated? |
Larger stimulus, AMPA depolarise membrane to expel Mg for NMDA |