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BM324: Fundamental Pharmacology > Block E Lecture 1 - GABA Systems > Flashcards

Block E Lecture 1 - GABA Systems Flashcards

1
Q

What is the main inhibitory neurotransmitter in the brain?

A

GABA

(Slide 4)

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2
Q

How is GABA synthesised?

A

It is synthesised from glutamate by glutamic acid decarboxylase (GAD)

(Slide 4)

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3
Q

Where is glutamic acid decarboxylase (GAD)?

A

In GABA-synthesising neurons in the brain

(Slide 4)

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4
Q

What are 4 examples of areas of the brain where GABA is found?

A

Striatum

Substantia Nigra

Hippocampus

Globus Pallidus

(Slide 5)

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5
Q

What are the 8 steps of synapse transmission?

A
  1. Neurotransmitters are synthesised and stored in vesicles
  2. Action potential arrives at the presynaptic terminal
  3. Voltage-gated Ca2+ channels open allowing influx of Ca2+
  4. Ca2+ allows vesicle docking and neurotransmitter release
  5. Neurotransmitter bins to receptors, causing channels to open (or close)
  6. Excitatory (or inhibitory) postsynaptic potential is generated
  7. Neurotransmitter is removed by glial uptake or enzyme degradation
  8. Vesicular membrane is retrieved from the plasma membrane

(Slide 6)

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6
Q

What terminates GABA action?

A

GABA transporter (GAT)

(Slide 7)

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7
Q

What are the 4 variants of the GABA transporter (GAT)?

A

GAT1
GAT2
GAT3
BGT1

(Slide 7)

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8
Q

What type of transporter are the GABA transporters?

A

Sodium ion symporters (Sodium goes down the concentration gradient, GABA goes up)

(Slide 7)

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9
Q

Where do the GAT1,2 and 3 and BGT1 transporters act?

A

GAT1 and 3 act in neuronal tissue whereas GAT2 and BGT1 act in non-neuronal tissue

(Slide 7)

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10
Q

How is GABA catalysed?

A

It is converted to succinate by GABA transaminase (GABA-T)

(Slide 7)

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11
Q

What are the 5 requirements for a substance to be considered a neurotransmitters?

A

Must be:

Synthesised in nerve terminals

Stored in nerve terminals (synaptic vesicles)

Released in a Ca2+ dependent manner

Acts on postsynaptic receptors

Is later removed / elimenated

(Slide 8)

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12
Q

What 2 descriptors can be applied to GABA binding to the brain?

A

Saturable ( there is a finite number of GABA receptors in the brain. Once all available receptors are occupied by GABA, no further binding can occur, regardless of how much GABA is present) and specific

(Slide 9)

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13
Q

What are the 2 main classes of GABA binding sites and what are the differences between them?

A

GABA receptors - binding is not sodium dependent

GABA uptake sites - binding is sodium-dependent, and they greatly outnumber the GABA receptor sites

(Slide 9)

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14
Q

What is the agonist rank of potency, to displace 3[H]-GABA?

A

Isoguavine > Muscimol > GABA > Gaboxadol (THIP)

(Slide 10)

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15
Q

What are 2 antagonists which have the ability to displace 3[H]-GABA and what are their properties?

A

Bicuculine - Displaces GABA but not from all receptors

Picrotoxin - Doesn’t displace GABA, it binds to the chloride ion channel pore of the GABA receptor

(Slide 10)

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16
Q

What are the 2 subtypes of GABA receptors, what are their properties and how was it confirmed that these subtypes exist?

A

GABAA - Bicuculine-sensitive and Baclofen-insensitive, ligand-gated (chloride) ion channel receptor

GABAB - Bicuculine-insensitive and Baclofen-sensitive, GPCR receptor

This is confirmed by the agonist baclofen [β-(4-chlorophenyl)-GABA] which is an agonist only at bicuculine-insensitive GABA sites

(Slides 11, 12 and 16)

17
Q

What is the structure of the subunits of the GABAA receptor, and how many subunits does the receptor have?

A

Subunits have 4 transmembrane domains, and the receptor is comprised of 5 subunits

(Slide 16)

18
Q

How is the chloride pore of the GABAA receptor formed?

A

By the TM2 domains of each of the subunits

(Slides 17 and 18)

19
Q

What 5 classes of GABAA receptor subunit isoforms exist?

A

α, β, γ, ρ and other

(Slide 19)

20
Q

What is the most common subunit arrangement of GABAA receptor?

A

2 X α, 2 X β and 1 X γ subunits

(Slide 19)

21
Q

How are GABAA receptors activated?

A

They have 2 interfaces between the α and β subunits, with GABA having to bin to both before the receptor becomes activated

(Slide 20)

22
Q

Where does benzodiazepine bind and what does it act as regarding GABAA receptors?

A

It binds at the interface between the α and γ subunits, activating as a positive allosteric modulator

(Slide 20)

23
Q

What is the structure of the GABAA-Rho receptor?

A

Also a 5 subunit ligand-gated ion channel, like normal GABAA receptors, but comprised solely of the three rho(ρ) subunit varieties

(Slide 21)

24
Q

What cells are GABAA-Rho receptors found in?

A

Retinal bipolar cells

(Slide 21)

25
Q

What is the GABAA-Rho receptor pharmacology?

A

It’s insensitive to: Bicuculine, barbiturates, benzodiazepine and baclofen

But it’s sensitive to: CACA (agonist), TPMPA (antagonist) and picrotoxin

(Slide 21)

26
Q

What is the structure of GABAB receptors?

A

It is a heterodimer made up ofGABAB1 and GABAB2 subunits, which each have 7 transmembrane domains each

(Slide 22)

27
Q

What do GABAB1 and GABAB2 receptors bind?

A

GABAB1 receptors bind GABA whereas GABAB2 receptors bind positive allosteric modulators

(Slide 22)

28
Q

What G protein do GABAB receptors couple to?

A

Gi/Go

(Slide 22)

29
Q

How does GABA cause presynaptic inhibition in the spinal cord?

A

It reduces transmitter release from the terminals of primary afferent fibres. It also involves axo-axonal synaptic connections (a GABA neuron connecting to a primary afferent fibre)

(Slide 28)

30
Q

How is GABA pharmacologically distinct from glycine?

A

Bicuculline and picrotoxin block GABA’s effects whereas strychnine blocks glycine’s effects

(Slide 28)

31
Q

How does GABA cause postsynaptic inhibition in the brain?

A

It increases chloride ion (Cl-) flux postsynaptically, resulting in the neuron becoming hyperpolarised, resulting in a decreased likelihood of the neuron firing an action potential

(Slide 30)

32
Q

How does the brain have a negative feedback system for dopamine?

A

Overactivity of dopamine results in an increase in GABA activity which results in the inhibition of dopaminergic firing in the substantia nigra

(Slide 31)

33
Q

What is an axon collateral?

A

It is a side branch which extends from an axon, allowing a neuron to communicate with multiple other neurons

(Slide 32)

34
Q

How can GABA inhibit a pyramidal neuron recurrently using axon collaterals, and how does this prevent epilepsy?

A

The axon collateral connects to GABA, with an interneuron and a GABA neuron also connecting to the pyramidal neuron.

1 A pyramidal neuron axon collateral activates a GABA interneuron

  1. The interneuron, in turn, inhibits firing of the pyramidal neuron
  2. This prevents a bursting discharge and reduces the max firing rate of the pyramidal cell.
  3. Bursting discharge is a feature of epilepsy, so preventing this stops epilepsy occuring

(Slide 32)

35
Q

How is recurrent inhibition measured?

A
  1. A pyramidal neuron is stimulated to fire an action potential.
  2. The resulting inhibitory postsynaptic potential (IPSP), caused by activation of inhibitory interneurons are recorded in the same neuron.
  3. The IPSPs can serve as evidence for recurring inhibition

(Slide 32)

36
Q

How do drugs effect the recurring inhibition of GABA?

A

GABA agonists (such as muscimol) enhance recurring inhibition, whereas GABA antagonists (such as bicuculine) depress it.

(Slide 33)

37
Q

What are the pre and postsynaptic effects of GABAB receptors?

A

Presynaptic: Decreased Ca2+ fluxes

Postsynaptic: Increased K+ fluxes

(Slide 36)

38
Q

What are GABAB receptors implicated as a target for management of?

A

Pain
Absence epilepsy (brief, sudden lapse of consciousness)
Cocaine addiction
Asthma

(Slide 36)

BM324: Fundamental Pharmacology (15 decks)

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