Synaptic transmissin
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| GABAergic synapse | 1. Synthesis
2. Storage
3. Metabolism - uptake and breakdown
4. Action - GABA receptors
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| GABA synthesis | From glutamate via glutamic acid decarboxylase (GAD) in cytosol.
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| GAD | Two forms: 67 and 65 preferentially located in nerve terminal
67: constitutively active saturated with PLP
65: apoenzyme with no PLP bound
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| GABA synthesis - drugs | 1. Hydrazides - react with PLP (i.e. eliminate)
2. ATP - inhibits activation of GAD by PLP
3. iP - promotes activation of GAD by PLP
4. Glu competitive inhibitors, e.g. allylglycine
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| GABA storage | From cytosol to vesicle via VGAT, proton driven transport.
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| GABA metabolism | 1. Uptake by GABA uptake T (GAT) - glial and neuronal
2. Breakdown by GABA transaminase (GABA-T) in mitochondria
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| GABA metabolism - drugs | 1. glial GAT inhibitor: B-alanine
2. neuronal GAT inhibitor: ACHC
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| GABAergic synapse | 1. Synthesis
2. Storage
3. Metabolism - uptake and breakdown
4. Action - GABA receptors
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| GABA synthesis | From glutamate via glutamic acid decarboxylase (GAD) in cytosol.
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| GAD | Two forms: 67 and 65 preferentially located in nerve terminal
67: constitutively active saturated with PLP
65: apoenzyme with no PLP bound
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| GABA synthesis - drugs | 1. Hydrazides - react with PLP (i.e. eliminate)
2. ATP - inhibits activation of GAD by PLP
3. iP - promotes activation of GAD by PLP
4. Glu competitive inhibitors, e.g. allylglycine
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| GABA storage | From cytosol to vesicle via VGAT, proton driven transport.
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| GABA metabolism | 1. Uptake by GABA uptake T (GAT) - glial and neuronal
2. Breakdown by GABA transaminase (GABA-T) in mitochondria
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| GABA metabolism - drugs | 1. glial GAT inhibitor: B-alanine
2. neuronal GAT inhibitor: ACHC
3. GABA-T inhibitor: sodium valproate and gamma-vinyl GABA (anticonvulsant)
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| GABA actions - GABA receptors | 1. GABAa - ionotropic (- bicuculline)
2. GABAb - metabotopic, baclofen (-2-OH-saclofen)
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| GABAa actions | - primary mediators of fast inhibitory synaptic transmission in the CNS, e.g. modify spike timing
- permit chloride and bicarbonate ions
- hyperpolarising or increasing cell conductance
- depolarising in immature neurons
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| GABAa R modulation sites | 1. Benzodazepine
2. Barbiturate
3. Anaesthetics - volatile and intravenous
4. Picrotoxin
5. Steroid
6. GABA
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| GABAa R structure | - Cyc-loop superfamily
- Pentameric ligand-gated channel
- 4 membrane spanning regions (M1-M4)
- M2 form pores
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| GABAa 7 subunits - subunit composition determines the functional properties and localisation (phasic and tonic) | 1) GABA affinity
2) activation and deactivation kinetics (duration of conductance change)
3) onset and recovery from desensitisation
4) single channel conductance (magnitude of conductance change)
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| GABA subunits e.g. A1B2Y2 (major: anticonvulsant and sedative actions of BZDs) e.g. A2B3Y2 (minor: anxiolytic action of BZDs) | A and B form functional receptors
+Y is required for BZD pharmacology
A determines the type
D associates with A4 and A6 : high affinity with (-)BZD
E related to Y, with ABY form insensitive to BZD
Pie related to B, (-)steroid
Theta to B1, (-)GABA
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| GABAa receptor composition | (A1-6) (B1-3) (Y1-3) and others
2A and 2B subunits and a fifth subunit belongs to any of the other classes
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| GABAa - phasic inhibition | - in synaptic cleft, producing IPSCs
- IPSC shape: activated rapidly, decayed slowly, and biphasically depending on intrinsic properties of GABAa-R (subunits)
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| GABAa - tonic inhibition | - non-synaptic communication (extrasynaptic)
- spillover neurotransmitters (ambient GABA)
- mostly ABD composition (Delta subunit), ideal for low concentration for sustained time period
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Created by:
JonLai
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