GABA Flashcards
Why is GABA important?
main inhibitory neurotransmitter in the CNS (10-40% of
neurons in cortex, hippocampus, and substantia nigra)
What is its cellular function?
- Increases the conductance of chloride ions across cell
membranes
What NT is similar to it?
Glycine
What enzyme converts glutamate to GABA?
GAD = Glutamatic acid decarboxylase
What is the name of the GABA transporter?
Vesicular GABA transporter
(VGAT)
What NTs does it work with?
GABA and glycine
What is VGAT’s function?
VGAT identifies both
GABAergic and glycinergic
neurons in the CNS
What do GABA inhibitors do?
Cause convulsive activity
What are the experimental GAD antagonists?
- allylglycine
Describe the effects of GAD inhibition
decreases GABA levels and leads to
convulsive activity
Where is GAT-1 found?
on neurons and
astrocytes
Where is GAT-2 and 3 found?
Principally astrocytic.
Describe tiagabine
A selective antagonist of GAT-1 and elevates GABA levels in the synapse.
- Approved as an adjunctive AED for epilepsy
Describe vigabatrin
Irreversible inhibitor of GABA-T and elevates GABA levels in the brain by blocking breakdown
Where is GABA generally found?
widely used in inhibitory interneurons throughout the brain
Describe chandelier cells
Chandelier cells of the cortex synapse onto the axonal initial segment of pyramidal cells
Describe basket cells
Basket cells of the cerebellum, hippocampus, and cortex form axo-somatic synapses onto target
cells
What are the 2 types of GABAergic synapses?
Axo-axonal and axo-somatic
What are Purkinje cells?
large GABAergic projection neurons of the cerebellum
What are the functions of Purkinje cells?
Provide the sole output of motor coordination from the
cerebellar cortex
What controls Purkinje cells?
GABAergic
interneurons
What is Holmes
cerebellar degeneration?
Degeneration of Purkinje neurons
What are the symptoms of Holmes
cerebellar degeneration?
Impaired fine hand movement, speech deficits, tremors, and ataxia while walking
Describe GABAergic control of motor initiation
- Medium spiny neurons comprise 90-95% of the neurons in the
striatum - Inputs from neocortex (all except visual and auditory)
- Outputs to globus pallidus and substantia nigra
- Involved in two pathways that control initiation of motor activity in the basal ganglia
Describe the direct pathway
Excitatory input (glutamatergic): cortex –>
medium spiny neurons (MSN) in striatum.
Inhibitory output: medium spiny neurons –> internal globus pallidus & substantia nigra pars reticula
(SNpr).
GABAergic MSN inhibit tonic inhibitory output from globus pallidus → ventral thalamus (VTh) and from SNpr → superior colliculus.
Disinhibits outputs:
VTh– excitatory projections to upper motor neurons of cortex
Superior colliculus– controlling eye saccades
Describe the indirect pathway
Medium spiny neurons project to the external
globus pallidus which forms a loop with the
subthalamic nuclei.
Subthalamic nuclei (STN) has excitatory
glutamatergic projections to the internal
globus pallidus.
Indirect pathway activation leads to
disinhibition of STN projections and thus
inhibition of motor output (dis-disinhibitory
pathway).
Describe the role of dopamine
Dopamine plays a gating role and balances activity between the direct and indirect pathways.
Why is the D1 pathway promoted over D2?
Activation of nigrostriatal dopamine
pathways
What happens in Parkinson’s?
In Parkinson’s the loss of dopaminergic
projections shifts activity to the indirect pathway.
Describe cholinergic interneurons
Cholinergic interneurons in the
striatum receive excitatory inputs from
the cortex.
Where do they act?
directly
on the direct pathway.
Describe early interventions in Parkinson’s
M4AChR antagonists and AChE
inhibitors are useful therapeutics in
early Parkinson’s as they compensate
for decreased dopaminergic input.
Describe GABAA receptors
- Ionotropic
Classic ligand gated ion channel permeable to Cl-
5 subunits form the channel pore
Originally characterized by sensitivity to bicucculine (comp. antagonist)
Describe GABAB receptors
- Metabotropic
G-protein coupled receptors
Gi– inhibits adenylate cyclase (↓ cAMP)
* Gβγ– opens G-protein coupled K+ channel (GIRK)
Originally characterized by sensitivity to baclofen (specific agonist)
What are the 4 GABAA receptor binding sites?
GABA, Benzodiazepines, Barbituates and Neurosteroids
What does the GABA binding site do?
binds two molecules of GABA at
the interface between α and β subunits
What does the benzodiazepine site do?
binds benzodiazepines
(tranquilizers) as positive allosteric modulators
What does the barbiturate site do?
binds barbiturates (sedative &
anxiolytics) as positive allosteric modulators
What does the neurosteroid site do?
binds endogenous
neurosteroids as positive or negative allosteric
modulators
What is picrotoxin?
a non-competitive channel blocker
Describe Pentylenetetrazol
- binds in the pore at the same site as picrotoxin and
was used as a convulsant for depression therapy - Discontinued due to high risks of spontaneous seizure
- Widely replaced with electroconvulsive therapy in 1939
What is the competitive antagonist of the GABA binding site?
bicucculine– potent convulsant
- Widely used in animal models of epilepsy
What is the the agonist of the GABAsite?
muscimol
What is fly agaric the source of?
muscarinic AChR agonist muscarine
GABAA agonist muscimol
What are the characteristics of fly agaric?
- Potent hallucinogen
- Induces macroscopia
- Perception of objects being larger than they are
What are the effects of fly agaric?
- Consumption of fly agaric has serious peripheral
side-effects due to muscarinic cholinergic effects at
NMJ and parasympathomimetic effects
What is Gaboxidol?
a synthetic version of muscimol with
reduced psychotropic effects
What are the characteristics of Gaboxidol?
- Anxiolytic and analgesic
- Potential insomnia treatment
Describe benzos
- Sedative-hypnotic, anxiolytic
- Diazepam (Valium) one of the best known
- Better safety margin than barbiturates
- Binding causes increased probability of pore
opening - High risks of drug interactions at the GABAA
receptor - Orphan receptor site:
- Endogenous ligand not known
- Proposed ligands include inosine, peptides
such as diazepam binding inhibitor/acyl-CoA
binding protein, and small molecules called
endozepines
Describe barbiturates
- Sedative-hypnotic, anaesthetic
- Phenobarbitol best known
- Narrow safety margin
- High potential for abuse
- High risk of overdose
- Binding prolongs open time of Cl- pore
- Used in physician-assisted suicide and euthanasia
- Sodium amytal (amobarbital) is a barbiturate
known as a ‘truth serum’ - Helps to circumvent inhibitions
What is ethanol?
potent positive allosteric modulator of GABAA binding
to a site on the transmembrane surface of the δ-subunit
What alcoholic
effects is GABA connected to?
it’s sedative, euphoric, and addictive effects
through modulation of GABAA
Describe GABAA’s affinity to ethanol
- Ethanol binds GABAA with very high affinity – binding even at doses that would be considered moderate, social levels
What is propofol?
- Propofol is a potent anaesthetic that interacts with the
transmembrane surface of the β-subunit of GABAA - Positive allosteric modulator that increases channel open time
Briefly describe GABAB receptors
- Primarily affect excitability by coupling to GIRK
- GIRK activation is inhibitory by allowing K+ efflux which hyperpolarizes the cell
- GABAA is responsible for fast, weak inhibitory postsynaptic potential (IPSP) signalling
- Reversal potential Cl- ~ -70 mV
- GIRK is responsible for slow, strong component of IPSP
- Reversal potential K+ ~ -90 mV
- Baclofen is a specific agonist of GABAB and is a muscle relaxant and antispastic
Describe GHB
a weak GABAB agonist
- Excitatory at the GHB receptor at lower doses → recreational drug use
- euphoria, disinhibition, empathogenic
- Inhibitory at GABAB at higher doses → ‘date rape drug’
- Sedation, nausea, dizziness, and unrouseable sleep
Describe GIRK
- K+ channel activated during GPCR signalling
- GIRK opens on binding of Gβγ (the otherwise regulatory component of the G-protein complex)
- K+ exits the cell causing hyperpolarization of the cell membrane
- GIRK signalling inhibits subsequent depolarizing stimuli
Describe GABAA rho receptor
- Insensitive to baclofen and
bicucculine– lacks binding sites for
benzodiazepines, barbiturates, and
neurosteroids - More sensitive to GABA (having 5
GABA binding sites) - Found in bipolar cells of the retina
- Receive inhibitory signals from amacrine
and horizontal cells - Mutations in GABAA-ρ are associated
with heritable cases of retinitis
Pigmentosa
Describe GABA development
late developmental
step and is associated with maturation of impulse control, working
memory, and executive function
Describe anxiety disorders
- E.g. Generalized anxiety disorder, social anxiety disorder, panic disorder, post-
traumatic stress disorder
What are the effects of GABA agonists and positive allosteric modulators on anxiety disorders?
Anxiolytic
Describe first anxiety and GABA model
Anxiety is caused by secretion of endogenous inverse agonists of GABAR →
inhibition of GABAR increases anxiety?
Describe second anxiety and GABA model
Ligand activity at GABAR is shifted in anxiety (subunit alterations?)
Describe third anxiety and GABA model
Secretion of endogenous agonists of benzodiazepine site during stressful
conditions → deficit in anxiety disorders?
Describe role of GABA in development
- High levels of GABA and developmental changes in GABA
activity (excitatory / inhibitory switch) - GABA may contribute to cell proliferation, survival, and motility
- Excitatory / Inhibitory balance is important in normal brain
development - E/I balance is affected in conditions such as Down’s syndrome and Autism
Describe link between GABA and epilepsy
- Excitatory / Inhbitory balance implicated in seizure disorders
- Drugs that decrease GABA levels or inhibit GABAR function are
convulsant - Drugs that increase GABA levels or increase GABAR function are
anticonvulsant - E/I imbalance in Down’s syndrome and Autism correlate with
increased risk of seizure disorders
Describe GABA and psychiatric disorders
- GABA has been implicated or suggested to play a role in numerous neuropsychiatric & neurodegenerative disorders
- Developmental disorders (ASD)
- Addiction
- Learning disorders
- Schizophrenia
- Tardive dyskinesia
- Huntington’s disease
- Parkinson’s disease
- Generally proposed to contribute to hyperactivity through decreased
inhibitory signalling
