GABA and Glycine Flashcards
Cocculus inicus and its case in the House of Commons
Hippo toxin is GABA receptor antagonist therfore important in beer
Making beer poor —> Cocculus indicus multum (an extract of coculus indicus)
“Malt, to produceintoxication, must be used in such large quantities as would very much diminish, if not totally exclude, the brewer’s profit.”
GABA is the main inhibitory transmitter in the adult nervous system:
- the major excitatory neurotransmitter is the precursor to the main inhibitory transmitter!
- GABA is synthesised by the enzyme glutamic acid decarboxylase (GAD)
- glutamate —> (GAD) —> GABA
- GAD (either 65 and/or 67) is localised specifically to GABAergic neurons
- GABA is present in highly diverse inhibitory interneurons (e.g basket, stellate, etc..) and projection neurons (e.g Purkinje) throughout the brain.
GABAergic transmission:
- GABA is transported back into GABAergic terminals via dedicated GABA transporters.
- It is also buffered by astrocytes where it is degraded by GABA transaminase (GABA-T).
- Thus, in GABAergic neurotransmission, there is a net flow of GABA from the neuronal to the astrocytic compartment.
- This net flow needs to be compensated by a flow of a GABA precursor in the opposite direction.
- GABA - Glutamate - Glutamine —> Glutamine goes back to presynaptic terminal
- Broken down by GABA-T
- Involves presynaptic terminals and
astrocytes - Pool of precursor becomes available, replenished for system to function
GABA-proteins
GAD - intracellular (GAD65-axon terminal, GAD67-cytosol) —> synthesises GABA
GABAT - mitochondria —> degenerated GABA
GAT (GAT1-neurons and glia, GAT2/GAT3-glia and periphery, GAT4-brain and periphery) —> transport GABA across plasma membrane
GABAA (𝛼, 𝛽, 𝛾, 𝛿, 𝜌 ,𝜋,𝜀) - postsynaptic membrane
—> iontropic receptor (chloride channel)
GABAB (R1, R2) - pre and postsynaptic membrane
—> Metabotropic receptor (G-protein linked)
Is there a GABAC?
The distinction between GABAA and GABAC receptors is based only on pharmacological grounds.
GABAC receptors are characterised by their activation by cis-4-aminobut-2-enoate (CACA), whereas classic GABAA receptor agonists such as isoguvacine have no effect.
Because the GABAC receptor is a homomeric complex of “rho”-subunits sharing a considerable amino acid sequence homology with the remaining GABAA receptor subunits, it may be concluded that this receptor subclass should be termed a pharmacologically distinct GABAA receptor.
GABAA agonists and antagonists
Agonists:
- GABA
- THIP
- Isoguvacine
- isoipecotic acid
- muscimol
Antagonists:
- Bicucilline
- Picrotixinin
GABAC agonists and antagonist:
Agonists:
- GABA
- CACA
- CAMP
Antagonists:
3-APMPA
3-APPA
Composition of GABAA & distribution (a1 and a2)
GABAA receptors are thought to be pentameric complexes, comprised of possibly more than 2000 different subunit combinations (~20 widely expressed; fewer dominant).
The most prevalent subunit in the brain is α1, with the major GABAA receptor subtype in brain having a stoichiometry of α1β2γ2.
Receptors containing the α2 subunit are most abundant in regions where the α1 subunit is absent or expressed at low levels, such as the hippocampus, striatum, and olfactory bulb.
Composition of GABAA & distribution (a3, a6)
The α3 subunit is expressed in regions
complementary to the α1 subunit, including the lateral septum, reticular nucleus of the thalamus, and brainstem nuclei.
The α6 subunit is expressed almost exclusively in cerebellum.
GABAA subunits
19 different subunits, in eight families. The 𝛼 family comprises 6, 𝛽 4, 𝛾 - 3 and 𝜌 - 3 subunits. Remaining 4 subunits (𝛿,𝜀,𝜃,𝜋) have only 1 splice variant identified.
𝛼, 𝛽, 𝛾, 𝛿, 𝜀 subunits can form heteromeric complexes.
GABAA/C receptor
Expressed in retina
Homomeric complex of 𝜌-subunits, resistant to both bicuculline and baclofen.
Binding sites on GABAA receptor:
GABA site - bicuculline (antagonist)
Benzodiazepine site - agonists (depressants e.g diazepam)
Barbiturate site - e.g pentobarbital
Steroid site - anaesthetics or axiogenics
Picrotoxin - convolusants
GABAB receptor
The metabotropic G protein-coupled GABA receptors, originally termed GABAB because they are pharmacologically distinct from GABAA (being activated by baclofen and insensitive to the GABAA receptor antagonist bicuculline).
Two subtypes, GABAB1 and GABAB2 have to form a heterodimeric complex in order to be functionally active. Postsynaptic GABAB receptors normally produce hyperpolarization due to coupling to K+ channels.
Presynaptically, GABAB receptors are coupled to Ca2+ channels, and activation leads to a decrease in Ca2+ conductance, resulting in inhibition of transmitter release. Thus, counterintuitively GABAB agonists can produce muscle relaxation and antagonists act as anti-epileptics.
GABAB synaptic transmission
GABAB receptor function regulates neurotransmitter release at both GABAergic and glutamatergic terminals.
Also bind to GABAB receptors - limiting further release of GABA - produces larger activation - where counter interaction comes in. Activation of GABAB receptors on these channels, decreasing their conductance function and decreases activation of excitatory neurons
GABAB receptors can inhibit their own action and also the receptors can inhibit other action
Positive and negative deflections during measurement of EPSPs and IPSP:
GABAB receptor function regulates neurotransmitter release in both GABAergic and glutamatergic terminals
* reduce release of glutamate
* Can be in dopaminergic terminals, not many on GABAergic terminals
GABAA&B receptors in synaptic plasticity
Under baseline conditions (a) activation of GABAA and GABAB receptors reduce the postsynaptic depolarisation, preventing NMDAR conductance.
During high frequency activation (b), decreased release of GABA results due to activation of presynaptic GABAB receptors leading to reduction of postsynaptic GABAA activation and thereby greater depolarisation and NMDAR conductance.
Example of how GABAB by inhibiting GABA can produce a greater excitation
