GABA Flashcards
1
Q
What is GABA
A
- THE principal inhibitory transmitter in the CNS (>30% of brain synapses)
- Activates both ionotropic and metabotropic receptors
2
Q
What is GABA synthesised from
A
- Enzymatic synthesis from glucose via Kreb’s cycle
3
Q
How is GABA inactivated
A
- Inactivated by reuptake by the GABA Transporters (GAT)
4
Q
What can deficits in GABA transmission lead to
A
- Deficits in GABA transmission important in epilepsy and anxiety
5
Q
What does glycine do
A
- Glycine also has a role as an inhibitory amino acid transmitter
6
Q
Describe the synthesis of GABA
A
- Starts with glucose and via krebs cycle the product is alpha-ketoglutamate
- Then glutamate which is converted to GABA using glutamic acid decarboxylase GAD
- GABA is transported into vesicles by VGAT- vesicular transporter
- When membrane terminal depolarises calcium enters, vesicles fuse with membrane and GABA is released
7
Q
Describe how GABA is terminated
A
- Action is terminated when taken out of synapse by GABA transporters into astrocytes where it is metabolised
- Also taken up to nerve terminals where it is either taken up by synaptic vesicles or converted by GABA-transaminase into succinic semialdehyde
8
Q
Describe the distribution of GABA
A
- 35% of neurones stain for Glutamic Acid Decarboxylase (GAD) – i.e. GABA neurones
- Not localized discretely
- GABA neurones play prominent role in cerebellum, basal ganglia, hippocampus, hypothalamus, cortex
- Principally in local interneurones- Connections limited to other neurones in local area
- Can be found in relay or projection neurones
9
Q
What is relationship with GABA and glutamate
A
- Balance each other out
2. GABA inhibits, glutamate excites
10
Q
Describe GABA(A) receptor
A
- ligand gated ion channels
- permeable to Cl- ions
- primarily postsynaptic
- mediate fast (milliseconds) inhibition
11
Q
Describe GABA(B) receptor
A
- G-protein-coupled receptors (GPCR)
- coupled to Ca2+ and K+ ion channels
- pre and postsynaptic
- mediate slow inhibition (seconds-minutes)
- also inhibit transmitter release
12
Q
Describe GABAC receptors (GABAA-rho (ρ) receptor)
A
- ligand gated Cl- channels
- postsynaptic mainly located in retina
- mediate fast (ms) inhibition
13
Q
Describe the fast synaptic inhibition caused by GABA(A)
A
- Low intracellular Cl-
- GABA opens channel
- inward negative Cl- current
- Membrane hyperpolarizes
- Inhibitory postsynaptic potential (IPSP)
14
Q
Describe the structure of GABA(A) receptor
A
- GABAA receptor subunits have 4 trans-membrane segments
- TM2 (one of 4 trans-membrane segments) is pore forming segment
- Functional receptors are pentameric combinations of different subunits arranged to form the integral ion channel
- Most prevalent receptor in mammalian brain consists of two α, two β and one γ-subunit
- GABA binds between α and β-subunits – so 2 molecules to activate receptor
15
Q
Describe different GABAA structures
A
- Multiple isoforms of α, β and γ subunits
- Rarer subunits exist – δ, ε, π, θ and ρ
- Most prevalent receptor is α1/β2/γ2
- Different subunits confer distinct physiological properties
- Receptor pharmacology is subunit-dependent
- Inhibitory effect depends on composition.
- Differential spatial distribution of receptors
16
Q
What are the binding sites of a GABA A receptor
A
- Benzodiazepine
- GABA
- barbiturate/anaesthetic binding site
- neurosteroid binding site
- channel blocking site
17
Q
Describe benzodiazepine binding site
A
- e.g. diazepam, lorazepam
- potentiate GABA
- increase frequency of channel opening
- anxiolytic (reduce anxiety), antidepressant, muscle relaxant
18
Q
Describe GABA binding site
A
- agonists: GABA, muscimol
- antagonists: bicuculline, gabazine
- At interface of alpha-beta subunits- 2 binding sites
19
Q
Describe barbiturate/anaesthetic binding site
A
- pentobarbital, thiopental, propofol
- potentiate GABA
- prolong open time of channel
- sedative, antiepileptic, anaesthetic
20
Q
Describe neurosteroid binding site
A
- derivatives of sex hormones
- increase or decrease
- endogenous GABA inhibition
- adjacent to barbiturate binding site
21
Q
Describe channel blocking site
A
- picrotoxin, pentylenetetrazole
- block Cl- permeability
- convulsant
22
Q
Describe action at GABAB receptors
A
- GABAB-receptors are Gαi/o coupled, 7-TM GPCRs
- Linked to K+-channels in postsynaptic neurones
- Linked to Ca2+-channels in presynaptic terminals
- Presynaptically- closes calcium channels to reduce transmitter release
- Postsynaptically- opens potassium channels eliciting a slow hyperpolarization
23
Q
What are the agonists and antagonists of GABAB recetpors
A
- Agonists: GABA, baclofen
2. Antagonists: 2-hydroxy- saclofen, CGP55845A
24
Q
Describe why functional GABAB receptors
are obligatory heterodimers
A
- Two GABAB-receptors GABABR1 + GABABR2
- R1 in endoplasmic reticulum
- R2 in cell membrane
- Neither is functional alone
- Dimerize via C-terminal to form functional GABABR
- R1 binds GABA not R2
25
Q
Describe the interactions of GABAA and GABAB receptors
A
- GABA can mediate fast and slow postsynaptic inhibition
- GABA can control its own release and strength of inhibition
- e.g. postsynaptic GABAA + presynaptic GABAB will lead to signal decreasing
26
Q
What are the therapeutic targets for GABAB receptors
A
- GABABR agonists (baclofen) for spasticity (muscle spasms, rigidity) in multiple sclerosis and related motor disorders
- Activates postsynaptic GABABR on motor neurones
- May also have sedative and anxiolytic effects - GABABR antagonists for possible use in epilepsy
- Blocks presynaptic GABABR on GABA neurones to prevent reduction of GABA release (can’t block Ca2+ channels now) and increase synaptic inhibition
- May also be sedative
