2003B03 Outline GABA’s role as a neurotransmitter and indicate how its actions
may be modified by pharmacological agents.

 

List:

·     GABA

·     GABA-A

·     GABA-B

·     Drugs

 

GABA: (γ-aminobutyric acid)

Type of neurotransmitter

·  Inhibitory

Location

·  Brain > spinal cord > peripheral sites

·  Especially hippocampus, other limbic structures, brainstem

Production

·  Glutamic acid -> GABA

·  Enzyme: glutamic acid decarboxylase

·  Cofactor: vitamin B6

Degradation

·  GABA -> glutamate or succinate

·  Enzyme: GABA transaminase (inhibited by some anticonvulsants)

 

GABA-A receptor:

Diagramme

Structure

·  Pentameric ligand-gated ion channel

·  α1β1α2β2γ

Location

·  Mostly post-synaptic

Activation

·  ↑Cl- conductance, prevention of action potential

·  (no hyperpolarization since RMP -70mV, Cl- Nernst potential -65mV)

·  Rapid onset and offset (milliseconds)

Subtypes

·  α1: sedation, amnesia, anticonvulsant

·  α2, α3: muscle relaxation, anxiolysis

 

GABA-B receptor:

Type

·  Metabotropic G protein coupled receptor

Location

·  Mostly pre-synaptic

Activation

·  ↑K+ efflux, hyperpolarization, ↓action potential

·  Slower onset (seconds) and offset

 

Drugs at GABA-A receptor:

Benzodiazepines

·  e.g. midazolam

·  Binds BDZ site at α-γ interface

·  ↑probability of adopting active conformation once GABA bound

·  Note flumazenil competitive antagonist at same site

Propofol

Thiopentone

Volatile agents

·  Bind A and/or B subunit

·  ↓rate of dissociation of GABA from its receptor

Baclofen

·  Derivative of GABA

·  Agonist at GABA-B

Gamma hydroxybutyrate

·  Precursor to GABA

·  Weak agonist at GABA-A

Alcohol

Etomidate

·  Unknown

 

 

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