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PHYS - NEURO > 4. GABA & GLYCINE > Flashcards

4. GABA & GLYCINE Flashcards

1
Q

What is GABA?

A
  • GABA is the major inhibitory neurotransmitter found in the CNS
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2
Q

How is GABA synthesised?

A
  • GABA is synthesized from Glutamate in the nerve terminals
  • Glutamate can be metabolised from glucose
  • Glutamate –> GABA by Glutamate decarboxylase
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3
Q

What enzyme is involved in GABA synthesis & what co-factor is needed?

A
  • Glutamate -> GABA by GLUTAMATE DECARBOXYLLASE

- Pyridoxal phosphate is the co-factor for Glutamate decarboxylase. The co-factor is derived from Vitamin B6

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4
Q

What is the transporter involved in transporting GABA into vesicles?

A
  • GABA is transported into vesicles by VIAAT (Vesicular inhibitory amino acid transporter)
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5
Q

What’s the difference between GABA & Glutamate storage in vesicles?

A
  • GLUTAMATE = VGLUT & round vesicles

- GABA = VIAAT & oval vesicles

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6
Q

What transporters are involved in re-uptake of GABA & what are the two types?

A
  • GAT (GABA re-uptake transporters) take up GABA from the synaptic cleft into the pre-synaptic neurone.
  • GAT are located on neurones & glial cells
    1. GAT1 = neurones
    2. GAT3 = glial cells
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7
Q

What two enzymes are involved in the degradation of GABA?

A
  • GABA is degraded by being converted to Succinic acid in two steps (two enzymes):
    1. GABA-T (GABA Transaminase)
    2. SSADH (Succinic Semi-aldehyde dehydrogenase)
  • GABA –> SUCCINIC SEMIALDEHYDE by GABA T
  • SUCCINIC SEMIALDEHYDE –> SUCCINIC ACID by SSADH
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8
Q

What are the two GABA receptors?

A
  1. GABA-A (IONOTROPIC/LIGR)

2. GABA-B 9METABOTROPIC/G-PROTEIN COUPLED)

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9
Q

What are the properties of GABA A receptors?

A
  • GABA A receptors are ligand gated Cl- ion channels
  • Binding of GABA to the GABA A receptor results in a chloride efflux, leading to hyperpolarisation
  • The hyperpolarisation of the membrane decreases the likelihood of action potential firing, as it increases the threshold for action potential firing
  • Therefore it has an inhibitory effect
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10
Q

What are the sub-units for GABA A receptor & the most common configuration?

A
  • The GABA A receptor has five sub-units
  • Most common: 2 alpha, 2 beta & one gamma
  • There are several sub-types: 6 alpha sub-types, 3 beta & 3 gamma sub-types
  • GABA binds at the interface between alpha & beta
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11
Q

Where does GABA & other drugs bind on the GABA A receptor?

A
  • The GABA A receptor has multiple binding sites making it a key drug target
  • GABA = binds between alpha & gamma
  • BENZODIAZEPINES = binds between alpha & gamma
  • PICROTOXIN - non-competitive antagonist that blocks the GABA A ion channel
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12
Q

What are the properties of the GABA B receptor?

A
  • The GABA B receptor is a G-protein coupled receptor
  • It is coupled to Gi/o so it’s negatively linked to adenylate cyclase resulting in decreased cAMP & therefore decreased Ca2+.
  • The GABA B receptor has an inhibitory effect
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13
Q

What are the two effects of the GABA B receptor & the consequence?

A
  1. Increase K+ efflux - G-protein signalling cascade activates potassium channels
  2. Decrease Ca2+ influx
    - Both of these effects result in hyperpolarisation. reducing the likelihood of action potential firing
    - Therefore, GABA B receptor has an inhibitory effect once activated
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14
Q

Define hyperpolarisation?

A
  • Hyperpolarisation refers to the displacement of teh membrane potential towards a more negative value.
  • This means that more stimulation is needed to reach the threshold for depolarisation
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15
Q

What is the cerebellum?

A
  • The cerebellum is a prominent hindbrain structure that is involved in detecting differences between the intended movement and the actual movement.
  • Help the motor cortex produce precise & controlled movement
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16
Q

What are the Purkinje cells of the cerebellum?

A
  • The Purkinje cells are the GABAergic projection of the cerebellum into the deep cerebellar cortex, which generates an error signal allowing movements to be modified
17
Q

What’s the importance of the GABA & Glutamate balance?

A
  • Glutamate is the major excitatory neurotransmitter
  • GABA is the major inhibitory neurotransmitter
  • Disruptions in the excitatory-inhibitory balance can lead to disorders or anxiety, migraines etc.
18
Q

What are two disorders that occur as a result of disrupted inhibitory & excitatory balance?

A
  1. ANXIETY
  2. EPILEPSY
    - A shift towards glutamatergic/excitatory neurotransmission can result in anxiety or epilepsy
19
Q

What is epilepsy?

A
  • Epilepsy is a brain disorder characterized by periodic & unpredictable seizures. It involves rhythmic firing of large groups of neurones
  • There’s too much glutamatergic neurotransmission, so it can be treated by increasing inhibitory neurotransmission or decreasing excitatory neurotransmission
20
Q

Give GABA-mediated treatments for epilepsy?

A
  1. GABA A enhancers - increase inhibitory neurotransmission
  2. GAT blockers - prevent re-uptake of GABA
  3. GAD MODULATORS - Increase activity of glutamate carboxylase which produces GABA from Glutamate
  4. GABA -T INHIBITORS - Prevent degradation of GABA
  5. PRODRUG - Administer a precursor of GABA which can be metabolised into GABA
21
Q

Give examples of GABA A receptor enhancers

A

GABA A enhancers - increase inhibitory neurotransmission, by increasing receptor activity to increase hyperpolarisation
E.g benzodiazepines & barbituates

22
Q

Give an example of GAT blockers?

A
  • prevent re-uptake of GABA, to increase circulating GABA

- E.g Tiagabine

23
Q

Give an example of GAD Modulators

A
  • E.g Gabapentin,Valproate

- Increase activity of glutamate carboxylase which produces GABA from Glutamate

24
Q

Give an example of a prodrug for GABA

A
  • E.g Progabide

- Can be metabolised into GABA

25
Q

Give an example of GABA-T inhibitors

A
  • E.g Vigabatrine

- Prevent degradation of GABA

26
Q

Describe the basis by which anxiolytic treat anxiety

A
  • Anxiety is caused by too much glutamatergic transmission, so it can be treated by increasing inhibitory neurotransmission
  • GABA A receptor enhancers such benzodiazepines & barbituates are used
27
Q

What is glycine?

A
  • Glycine is the second major inhibitory neurotransmitter after GABA
  • It is found mainly in the ventral horn
28
Q

How is glycine synthesised?

A
  • Glycine is synthesized from serine
  • But serine is metabolised from 3 -phosphoglycerate from glycolysis
  • Serine –> Glycine by SERINE HYDROXYMETHYTRANSFERASE
29
Q

What enzyme is responsible for glycine synthesis?

A
  • SERINE HYDROXYMETHYTRANSFERASE

- It is involved in both the synthesis & degradation of glycine

30
Q

Which transporters are involved in transporting glycine into vesicles?

A
  • Glycine is stored in oval vesicles

- It is packaged into vesicles by VIAAT (Vesicular Amino-acid transferase)

31
Q

Which transporters are involved in the re-uptake of Glycine?

A
  • Glycine is taken up from the synaptic cleft into teh pre-synaptic neurone by GlyT (Glycine re-uptake transporters)
  • The GlyT are found on neurones & glial cells
  • GlyT1 = glial cells
  • GlyT2 = neurones
  • Mutations in these transporters can lead to hypoglycaemia
32
Q

How is glycine degraded?

A
  • Glycine is converted to serine by SERINE HYDROXYMETHYLTRANSFERASE
33
Q

What enzyme is involved in the synthesis & degradation of glycine?

A
  • SERINE HYDROXYMETHYLTRANSFERASE
34
Q

Describe the structure of the glycine receptor & the most common configuration

A
  • The glycine receptor is a LIGR Cl- ion channel
  • the glycine receptor is located on the post-synaptic & pre-synaptic membrane
  • Glycine receptor has a pentameric structure
  • It consists of 5 sub-units
  • Most common: 3 alpha, 2 beta or 4 alpha, 1 beta
35
Q

What’s the effect of the glycine receptor?

A
  • Glycine binding to the glycine receptor leads to an influx of chloride resulting in hyperpolarization
  • The hyperpolaristaion decreases the likelihood of an action potential firing, resulting in an inhibitory effect
36
Q

What other receptor can glycine bind to?

A
  • Glycine can also bind to the NMDA receptor

- Glycine can bind to the GLuN1 whilst glutamate binds to the GLuN2 subunit of the NMDA receptor

37
Q

What is hyperekplexia & how does it occur?

A
  • HYPEREKPLEXIA is characterised by hypermyotonia which is increased muscle tone leading to an exaggerated startled response
  • Mutations can disrupt normal glycinergic neurotransmission. This leads to hyperexcitability due to the impaired glycinergic inhibition
38
Q

What happens in myotonic goats?

A
  • In myotonic goats there’s decreased muscle chloride conductance. Normally a chloride influx causes hyperpolarisation, but glycine receptor mutation can affect whether this occur
  • As the goats get older, their GABA A receptors will be upregulated to increase inhibition & to replace the impaired chloride conductance

PHYS - NEURO (18 decks)

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