Inhibitory Transmission Flashcards
1
Q
What is the GABA A receptor
A
- a transmitter gated anion channel
- pentamer
- major inhibitory receptor
- mediates “fast” inhibition in spinal cord alongside glycine
- proconvulsant and anxiogenic (panic)
2
Q
What drugs act on GABA A receptor
A
- positive allosteric modulators (PAMs), e.g. diazepam
- target for general anaesthetics
3
Q
What is the GABA B receptor
A
- a GPCR
- heterodimer
4
Q
What drugs act on GABA B receptor
A
- Baclofen
- selective agonist used to treat muscle stiffness arising from multiple sclerosis and spinal cord injuries
- acts on spinal cord
5
Q
What is GABA-T
A
- GABA transaminase
- converts alpha-ketoglutarate to glutamate in step 1 of inhibitory GABA-ergic transmission
6
Q
What is GAD
A
- glutamic acid decarboxylase
- converts glutamate to GABA in second step of inhibitory GABA-ergic transmission
7
Q
What blocks the GABA transporters GAT 1-3
A
tigabine (anti-convulsant)
8
Q
What is VGAT
A
- vesicular GABA amino acid transproter
- vacuums and concentrates GABA in vesicles
9
Q
Describe feed-forward inhibition
A
- invovles bi-synaptic inhibitory response
- activation of glutamate-gated cation conducting channels produce an excitatory postsynaptic potential (EPSP)
- activation of GABA-gated anion conducting channels produce an inhibitory postsynaptic potential (IPSP)
- control firing rate of neurons
10
Q
Describe feed-back inhibition
A
- firing of the pyramidal neuron activates inhibitory interneuron, which inhibits pyramidal neuron
- once inhibition decays pyramidal neuron can fire again
- circuits can generate neuronal oscillations (rhythmic activity) involving coordinated activity of principle neurons and interneurons
- interfering with balance causes dramatic effects on learning and memory
11
Q
What does the Gi alpha subunit do
A
inhibits adenylate cyclase (AC) activity to decrease cAMP levels
12
Q
Effects of postsynaptic GABA B activation
A
causes Gi BY complex to open K+ channel, causing slow hyperpolarisation
13
Q
Effects of presynaptic GABA B activation
A
causes Go BY complex to decrease the probability of voltage-gated Ca channel opening, and therefore decreases quantal release of neurotransmitter
14
Q
Define the term “phasic inhibition”
A
mediated by synaptically-localized receptors with a low affinity for GABA, results in a transient, rapidly desensitizing GABAergic conductance
15
Q
Role of B1 GABA B receptor subunit
A
provides GABA binding domain
16
Q
Role of B2 GABA B receptor subunit
A
provides G-protein coupling to G-alpha-i and G-alpha-o
17
Q
The GABA A receptor can be used as a therapeutic target for which drugs
A
- hypnotic and anxiolytic drugs
- benzodiazepines
- barbiturates
18
Q
How do benzodiazepines and barbiturates act on GABA A receptor
A
- benzodiazepines increase probability of channel opening (energetically unstable state)
- barbiturates promote channel open states of long duration
- barbiturates at higher concentrations directly activate the receptor
- at high doses, barbiturates, propofol and etomidate induce an anaesthetic state, whereas benzodiazepines do not
19
Q
Using Xenopus laevis to close GABA A receptor subunits
A
- led to unexpected diversity of subtypes
- 19 different subunits in brain
- rules governing which subtypes can get together with who and are located in different parts of brain
- alpha1-6
- gamma 1,2
- beta 1-3
20
Q
Receptor isoforms of GABA A
A
- distinct physiology, pharmacology, and exhibit a heterogeneous expression pattern in the CNS
- not uniformly expressed, found in various locations throughout nervous system
21
Q
Diazepam enhances the function of which GABA A receptor subunits
A
- alpha1, alpha2, alpha3, alpha5
- H residue at position 101
- alpha4 and alpha6 have R residue at this position
22
Q
Mutation of R101 to H on alpha6 subunit
A
produces a diazepam-sensitive receptor
23
Q
What was found in the alpha1H101R mouse
A
- alpha1 mutation causes loss of 3H-flumazenil binding in areas known to express alpha1 subunit
- dizaepam is not sedative, but anxiolytic
24
Q
Diazepam in alpha2H101R mouse
A
no longer anxiolytic but is sedative
25
How do general anesthetics produce side effects
- act on neuronal membrane
- enhance GABA A receptor function
26
Where is the GABA recognition site on GABA A receptors
between alpha and beta subunits
27
Where is the benzodiazepine binding site on the GABA A receptor
- between alpha and gamma subunits
- not at GABA recognition site, so does not open channel
28
Beta subunnit "knock in" anaesthetic-insensitive mice
- Etomidate is selective for GABA A receptors incorporating B2, B3 subunits
- beta subunit specificity dictated by single amino acid located in TM2
29
Effects of etomidate (anaesthetic agent) on a B2 N265S mutation
reduced GABA A receptor enhancing effects, prevented sedative effects, impaired hypotic action
30
Effect of etomidate and propofol on the B3 N265M mutation
reduced GABA A receptor enhancing effects and greatly impaired hypnotic action
31
What are neurosteroids
endogenous positive allosteric modulators (PAMs) of the GABA A receptor
32
What evidence suggests that neurosteroids made in the CNS act to influence neural inhibition and behaviour
Administration of neurosteroids to rodents produced anxiolytic, analgesic, anticonvulsant and sedative behaviours
33
How can neurosteroids fine-tune neural inhibition to influence mood and behaviour
- anxiolytic
- sedative
- hypnotic
- analgesic
- anticonvulsant
- antidepressant
34
GABA A receptor alpha2 Q241W mouse
- impairs neurosteroid enhancement of GABA responses mediated by alpha2-GABA A receptors
- inhibitory GABA A receptor-mediated mIPSCs in the hippocampus of the exhibits a reduced duration
- exhibits anxiogenic phenotype and exhibits reduced sensitivity to anxiolytic effects of 5alpha3alpha
- presence of neurosteroid tone sufficient to influence synaptic alpha2-GABA A receptors and behaviour
35
Brexanolone (neurosteroid) in pregnancy
- Animal studies have revealed evidence of decreased body weight, decreased pup viability, developmental toxicity, female offspring neurobehavioral deficit, lower pup survival, post-implantation loss, reproductive toxicity
- PPD associated with reduced expression of GABA A receptors
- causes sedation and can go unconscious -> infused with IV for 60 hours
36
What is the strychnine-sensitive glycine receptor (nAChR family) responsive to
- propofol
- glycine, tauring, strychnine
- volatile anaesthetics and alochols
37
What is GlyT1
astrocytic glycine transporter
38
What is GlyT2
neuronal glycine transporter
39
What is VIAAT
vesicle inhibitory amino acid transporter
40
What is strychnine
- obtained from poisonous nuts of the strychnine-tree
- potent competitive antagonist
- enhances perception of pain
- causes convulsions
41
Effects of mutations of the glycine receptor
- hyperekplexia (startle reaction)
- neonatal hypertonia
- variable incidence of apnoea
- intellectual disability and delays in speech acquisition
42
Define the term "tonic inhibition"
mediated by extrasynaptic receptors with a high affinity for GABA, results in a persistent GABAergic conductance
43
Role of GABA in mediating feed-forward inhibition
GABA limits window for generation of AP as it arrives only 1-5msec after glutamate input
44
Which subunit of GABA A receptor is responsible for sedation
alpha1
45
Which subunit of GABA A receptor is responsible for anxiety
alpha2 or alpha3
46
Side effects of Benzodiazepines
- drowsiness, dizziness, decreased concentration, impairment of motor coordination
- mild muscle relaxation as result of action on spinal cord, cerebellum, and brain stem
47
Side effects of Barbiturates
- dizziness, lightheadedness, sedation, memory and attention impairments
48
Binding site of Barbituates
alpha or beta subunit
49
Why must doses of Barbiturates be closely monitored
- at high doses, can mimic GABA and act directly on GABA receptors, causing profound nervous system depression
- toxic dose is not much higher than therapeutic dose (narrow therapeutic index)
