3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.4. Physiology
                  3.1.4.2. Neurophysiology
                      3.1.4.2.5. Gamma-aminobutyric acid (GABA)
 3.1.4.2.5.1. GABA receptors 

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

GABAA 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

GABAB 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)

GABAc receptor

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