GABA receptors

[WG21:p34-p35,p111; RD5:p26-p45,p470-p473]

• 3 types of GABA receptors
  * GABAa receptors = ligand-gated ion channels
  * GABAb receptors = G-protein coupled receptors
  * GABAc receptors = ligand-gated ion channels

GABA_A receptors

Structure

• Pentameric (5 subunits)
• Consists of:
  * The GABA-binding site (the receptor site)
  * Modulatory sites (including the benzodiazepine receptor and other modulatory sites)
  * An ion channel (chloride)
• A ligand-gated ion channel
  * Ligand = GABA
  * Channel = Anions, especially Cl-

Location

• Widespread in CNS
• Mainly GAGA-ergic interneurons

Agonists and antagonists

• At the receptor sites:
  * GABA is the endogenous agonist
  * Muscimol (derived from a hallucinogenic mushroom) is also an agonist
• Benzodiazepine receptor site:
  * Benzodiazepine binds to an accessory site (the benzodiazepine receptor) on GABAa receptor
  * Benzodiazepine receptor sites are on the alpha subunits [SH4:p141]
  * Allows facilitation of GABA binding to the receptor
  * Benzodiazepine does NOT directly activate GABAa receptor [SH4:p140]
  * Flumazenil is an antagonist at this site
• Agonists at other modulatory sites:
  * Barbiturates
  * Metabolites of progesterone and deoxycorticosterone [WG21:p112]
  * Steroid anaesthetics (e.g. alphaxolone)
  * Propofol [???]
  * Volatile anaesthetics [???]
• Chloride channel:
  * Picrotoxin can directly block the chloride channel associated with GABAa receptor

NB:

• Alphaxolone is a synthetic neurosteroid, developed as an anaesthetic agent [RD5:p471]
• Propofol and barbiturates decrease the rate of dissociation of GABA from GABAa receptors
  --> Duration of Cl- channel opening is prolonged [SH4:p128]
• Barbiturate may also mimic action of GABA and directly activate GABAa receptors [SH4:p128]

Function

• Binding of GABA
  --> Opening of the ion channel
  --> Inflow of Cl-
  --> Hyperpolarisation

Anaesthetic and GABAa receptors

[SH4:p21]

• Complete anaesthetic cannot be provided by GABAa-agonist actions of hypnotic drugs
  * e.g. benzodiazepines, barbiturates, propofol, etomidate
• Opioids and alpha2 agonists inhibits presynaptic calcium ion channel
  --> Presynaptic neurotransmitter release

Thus,

• Combination of activation of GABAa and inhibition of presynaptic calcium channel
  --> Full anaesthetics
• Volatile anaesthetics may provide both

GABA_B receptor

[RD5:p471-p472]

• GABAb receptor is a G-protein-coupled receptor
  --> Inhibition of adenylate cyclase [RD5:p472]
  --> Increase K+ conductance and decrease Ca2+ conductance [WG21:p112; RD5:p471]
• Structure:
  * A dimer with 2 different subunits (apparently that is unusual)
• Location:
  * Presynaptic
  * Postsynaptic
  * c.f. GABAa is only postsynaptic
• Function:
  * Increased K+ conductance --> Reduced postsynaptic excitability (postsynpatic action)
  * Inhibition of voltage-gated Ca2+ channel --> Reduced neurotransmitter release (presynaptic action)

GABA_c receptor

• GABAc is ALSO ligand-gated ion channel
  * Found almost exclusively in the retina
  * [WG21:p111]