Flashcards in GABA Deck (21):
In presynaptic neuron. Glu converted to GABA by glutamic acid decarboxylase (GAD)
Immediately packaged into vesicles by vGAT (processes are coupled)
GAT1-3 transporters on membranes of presynaptic neurons and glia.
If presynaptic neuron then packaged straight back into vesicles by vGAT.
GABA degradation (GABA "shunt")
Broken down by GABA-T (GABA transaminase) into succinic acid (goes back into Krebs cycle which produces Glutamate).
Glu then converted to GABA by GAD.
Ligand-gated Cl- channel.
19 possible subunits, most common config a2B2y
a/B interface is GABA binding site, needs two to cause conformational change which opens pore.
Postsynaptic locations, influx of Cl- hyperpolarises neuron and causes IPSPs so inhibitory.
Apart from during development: excitatory.
Metabotropic GPCR. Gi/Go = inhibitory G proteins. GABA binds and causes intracellular signalling cascade.
Mainly presynaptic locations.
Decrease cAMP and adenylate cyclase.
Coupled to K+ channels which open to allow K+ to leave cell = hyperpolarisation.
Therefore VG-Ca2+ channels in presynaptic membrane close so less Ca2+ into presynaptic neuron and less NMDA activity.
Inhibitory feedback mechanism to modulate depolarisation of presynaptic neuron in response to APs and therefore modulate release of GABA into synaptic cleft.
Cortical excitatory:inhibitory balance.
Optimum homeostatic balance between Glu and GABA = optimal cognitive function.
Epilepsy = shift in excitation:inhibition balance so increased excitatory tone, leads to increased seizure activity.
Inhibit GAD = convulsions.
Overexpression of GABA-T in mice = increased susceptibility to seizures (GABA taken back up into presynaptic neurons more quickly).
fMRI to visualise seizure focus. Could see in frontal lobes of patient.
Widespread synchronous neuronal discharge.
Can experience aura beforehand (heightened perceptions, hallucinations)
Tonic-clonic = muscle rigidity for 1 min then synchronous muscle jerking (myoclonic) for 2-3 mins.
Absence = momentary lapse of consciousness, muscle tone may be preserved.
Focal discharge which stays localised to one part of brain. Symptoms depend on part affected.
Can be simple or complex (depending on if memory, consciousness etc preserved)
Bind to BDZ allosteric site on GABAA, modulates how GABA activates receptor.
Increases affinity of GABA binding so increases frequency of channel openings and therefore potentiates GABA transmission.
Not really used anymore due to high addictive potential.
But diazepam can be infused for status epilepticus.
Bind to allosteric site on GABAA.
Stabilise open state of Cl- channel so stays open for longer (alters channel kinetics).
Not really used anymore due to abuse potential and very narrow therapeutic window esp if combined with other drugs that modulate GABAA e.g. alcohol, propofol.
Designed as lipid soluble analogue of GABA so could partition into membrane and activate postsynaptic GABARs. However not thought to actually exert its action this way.
Instead, binds to a2δ1 receptor which modulates synaptogenesis of excitatory CNS synapses. So reduces excitatory tone.
Also may bind to amino acid transporters so clears Glu more rapidly from synaptic cleft.
Adjunctive therapy only.
Pregabalin = prodrug, less taken up by metabolism.
Gabapentin binds to a2δ1 receptor which modulates synaptogenesis of excitatory CNS synapses. So reduces excitatory tone.
Analogue of GABA, binds to GAT1-2 so inhibits reuptake of GABA into neurons and glia.
Enhances GABA transmission at synaptic cleft.
Drowsiness, confusion (sedative effects).
Irreversibly inhibits GABA-T so increases releasable pool of GABA in presynaptic neurons.
Can cause depression and psychotic disturbances due to alteration of E:I balance (but rare).
tDCS for epilepsy
Shown to alter E:I balance (Krause 2013)
Cathodal tDCS could help epilepsy by lowering membrane potential of excitatory pyramidal neurons in cortex so decrease excitatory transmission / glutamatergic tone.
Small subcortical area found in epileptic patients where GABA has excitatory action (reverted to "immature" developmental function) during epileptogenesis.
Important consideration when prescribing AEDs.
First line, effective in controlling generalised epilepsy, and absence, tonic-clonic and myoclonic seizures.
Can also be used in children.
Enhances postsynaptic GABAB action.
Weakly inhibits GABA-T.
Some inhibition of Na+ channels so lower excitatory tone.
Well tolerated generally although is teratogenic and can cause hepatotoxicity.
Multiple modes of action:
GABA potentiation, AMPA / Glu inhibition, Na+ and Ca2+ channel blocker.
Partial and generalised seizures.
Although not as effective as some other first line drugs for new onset focal seizures.