GABA Flashcards
GABA is the main
inhibitory neurotransmitter in the CNS (10-40% of
neurons in cortex, hippocampus, and substantia nigra)
GABA increases the
conductance of chloride ions across cell
membranes
Glycine has
comparable but limited function as an inhibitory
neurotransmitter
Gaba synthesis
glutamate –(GAD)–> GABA
Vesicular transport GABA and glycine share a
vesicular transporter
GABA and glycine share a
vesicular transporter
Vesicular GABA transporter (VGAT) or vesicular inhibitory
amino acid transporter (IAAT)
- VGAT identifies both
GABAergic and glycinergic
neurons in the CNS
Inhibitors of GABA are
convulsants
GAD has several antagonists used experimentally (3)
allylglycine, thiosemicarbazide, and 3-mercaptopropionic
acid
Inhibition of GAD
decreases GABA levels and leads to
convulsive activity
Many drugs that decrease GABAergic activity are
limited in use to in vitro studies
GABA Transporters (GAT) are
found on
astrocyte and neuronal
membranes at the synapse
GAT-1 is located on
neurons and
astrocytes
GAT-2 and -3 are principally
astrocytic.
GABAergic AEDs Tiagabine
is a selective antagonist of GAT-1 and elevates GABA
levels in the synapse.
- Tiagabine (Gabitril) is
approved as an adjunctive AED for epilepsy
GABAergic AEDs Vigabatrin
is an irreversible inhibitor of GABA-T and elevates GABA
levels in the brain by blocking breakdown
Vigabatrin (Sabril) is approved as
an adjunctive or primary AED for
epilepsy
GABA is
widespread through the brain
GABA is widely used in
inhibitory interneurons throughout the brain
- Chandelier cells of the cortex
synapse onto the
axonal initial
segment of pyramidal cells
- Basket cells of the cerebellum,
hippocampus, and cortex form
axo-somatic synapses onto target
cells
GABAergic neurons form
multiple
types of synapses
- In addition to axo-dentritic
synapses GABAergic
synapses are often
axosomatic or axo-axonal
Axo-somatic synapses
control
excitability of cell body
Axo-axonal synapses
synapses at the
axon intial segment influence
signal integration
GABAergic output from the cerebellum
Purkinje cells are large GABAergic projection neurons of
the cerebellum
- Purkinje cells are large GABAergic projection neurons of
the cerebellum
Provide the sole output of motor coordination from the
cerebellar cortex
Purkinje cells are under
inhibitory control from GABAergic
interneurons
Degeneration of Purkinje neurons is termed
d Holmes
cerebellar degeneration
Holmes
cerebellar degeneration
Impaired fine hand movement, speech deficits, tremors, and
ataxia while walking
GABAergic control of motor initiation Direct pathway
Excitatory input from cortex causes
excitation of upper motor neurons
in motor cortex
GABAergic control of motor initiation Indirect pathway
Excitatory input from cortex causes
inhibition of upper motor neurons in
motor cortex
Dopaminergic
balance
Dopamine plays a gating role and balances
activity between the direct and indirect
pathways
Activation of nigrostriatal dopamine
pathways promotes the
direct pathway over the indirect pathway
In Parkinson’s the loss of dopaminergic
projections shifts activity to the
indirect
pathway.
Cholinergic balance
Cholinergic interneurons in the
striatum receive excitatory inputs from
the cortex
Cholinergic interneurons act directly
on the
direct pathway
M4AChR antagonists and AChE
inhibitors
are useful therapeutics in
early Parkinson’s as they compensate
for decreased dopaminergic input.
GABA Receptors Two classes of GABA receptors
Ionotropic (GABA_A),
Metabotropic (GABAB
Ionotropic (GABAA) Classic
ligand gated ion channel permeable to Cl-
Ionotropic (GABAA) 5
subunits form the channel pore
Ionotropic (GABAA) Originally characterized by
y sensitivity to bicucculine (comp. antagonist)
Metabotropic (GABAB what type of preitein coupled receptors?
G-protein coupled receptors
Metabotropic (GABAB
) Gi
inhibits adenylate cyclase (↓ cAMP)
Metabotropic (GABAB Gβγ
opens G-protein coupled K+ channel (GIRK
Metabotropic (GABAB
) Originally characterized by
sensitivity to baclofen (specific agonist)
GABAA * Pentameric channel
(5
-subunits) through
combination of 19 different genes`
how many types of alpha subunits
6 (GABARA1-6)
how many types of beta subunits
3 β (GABARB1-3)
how many types of gamma subunits
3 γ (GABARG1-3)
how many types of other subunits
One each of δ (GABARD), ε (GABARE),
θ
(GABARQ),
π (GABARP)
how many types of p subunits
3
ρ (GABARR)*
Most common GABA
A channel
Most common is
α2β2γ
Special case is GABA
Aρ which only forms
homopentameric channels with itself
GABAA has ___ binding sites for
4, endogenous
and exogenous ligands
GABAA has 4 binding sites for endogenous
and exogenous ligands GABA site
binds two molecules of GABA at
the interface between α and β subunits
GABAA has 4 binding sites for endogenous
and exogenous ligands Benzodiazepine site
binds benzodiazepines
(tranquilizers) as positive allosteric modulators
GABAA has 4 binding sites for endogenous
and exogenous ligands Barbiturate site
– binds barbiturates (sedative &
anxiolytics) as positive allosteric modulators
GABAA has 4 binding sites for endogenous
and exogenous ligands Neurosteroid site
binds endogenous
neurosteroids as positive or negative allosteric
modulators
Picrotoxin
is a non-competitive channel
blocker
GABAA pharmacology Non-competitive sites
Pentylenetetrazol
Pentylenetetrazol
l binds in the pore at the same site as picrotoxin and
was used as a convulsant for depression therapy
Pentylenetetrazol Discontinued due to
high risks of spontaneous seizure
GABAA pharmacology GABA site Competitive antagonist is
bicucculine
bicucculine
potent convulsant
GABA site Classic agonist is
muscimol
Amanita muscaria (fly agaric)
Source of the muscarinic AChR agonist muscarine
Source of the GABAA agonist muscimol
Potent hallucinogen
Consumption of fly agaric has serious
peripheral
side-effects due to muscarinic cholinergic effects at
NMJ and parasympathomimetic effects
Gaboxidol is a
synthetic version of muscimol with
reduced psychotropic effects
Anxiolytic and analgesic
Investigated for insomnia treatment
Benzodiazepines
Sedative-hypnotic, anxiolytic
Diazepam
Benzodiazepines (Valium) one of the best known
Benzodiazepines
Better safety margin than
barbiturates
Benzodiazepines Binding
causes increased probability of pore
opening in creased chloride entering the cell
Benzodiazepines High risks of drug interactions at the
GABAA
receptor
Benzo 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
Barbiturates
Sedative-hypnotic, anaesthetic
Barbiturates best known
Phenobarbitol
Barbiturates Narrow
safety margin
Barbiturates Narrow safety margin
High potential for abuse
* High risk of overdose
Barbiturates Binding prolongs open time of
Cl- pore
Barbiturates Used in
physician-assisted suicide and
euthanasia
Barbiturates Sodium amytal (amobarbital) is a
barbiturate
known as a ‘truth serum’
Sodium amytal (amobarbital) is a barbiturate
known as a ‘truth serum’
Helps to circumvent inhibitions
Other notable interactions of GABAAR Ethanol
is a potent positive allosteric modulator of GABAA binding
to a site on the transmembrane surface of the δ-subunit
Ethanol exerts many of it’s
sedative, euphoric, and addictive effects
through modulation of GABAA
Ethanol binds
GABAA with very high affinity – binding even at doses that
would be considered moderate, social levels
Propofol is a potent
anaesthetic that interacts with the
transmembrane surface of the β-subunit of GABAA
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
GABAB
receptors * Primarily affect excitability by
coupling to
GIRK
GIRK activation is
s inhibitory by
allowing K+ efflux which
hyperpolarizes the cell
GABAA is responsible for
fast, weak
inhibitory postsynaptic potential (IPSP)
signalling
GIRK is responsible for
slow, strong
component of IPSP
Baclofen is a specific
agonist of
GABAB and is a muscle relaxant
and antispastic
γ-hydroxybutyric acid (GHB) is a
weak GABAB agonist
γ-hydroxybutyric acid (GHB) is a
weak GABAB agonist Excitatory at the
GHB receptor at
lower doses → recreational drug use
γ-hydroxybutyric acid (GHB) is a
weak GABAB agonist
* Excitatory at the GHB receptor at
lower doses → recreational drug use
euphoria, disinhibition, empathogenic
γ-hydroxybutyric acid (GHB) is a
weak GABAB agonist Inhibitory at
GABAB at higher doses →
‘date rape drug’
Sedation, nausea, dizziness, and
unrouseable sleep
G-protein coupled inward rectifying
K
+ channel (GIRK) K
+ channel activated during
GPCR
signalling
G-protein coupled inward rectifying
K
+ channel (GIRK) GIRK opens on binding of
Gβγ (the
otherwise regulatory component of
the G-protein complex)
G-protein coupled inward rectifying
K
+ channel (GIRK) K
+ exits the cell causing
hyperpolarization of the cell
membrane
G-protein coupled inward rectifying
K
+ channel (GIRK) * GIRK signalling inhibits
subsequent
depolarizing stimuli
GABAA
-ρ (rho) Receptor
– formed exclusively as a
homopentamer of the ρ-subunit (Clchannel)
GABAA
-ρ (rho) Receptor Formerly considered
GABAC receptor
GABAA
-ρ (rho) Receptor Insensitive to
baclofen and
bicucculine
baclofen and
bicucculine
lacks binding sites for
benzodiazepines, barbiturates, and
neurosteroids
GABAA
-ρ (rho) Receptor * More sensitive to
GABA (having 5
GABA binding sites)
GABAA
-ρ (rho) Receptor Found in
bipolar cells of the retina
GABAA
-ρ (rho) Receptor 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
Bipolar cells
(express
GABAA
-ρ )
Amacrine cells Horizontal cells
Inhibitory neurons
(GABAergic)
GABA development in the prefrontal cortex is a
late developmental
step and is associated with maturation of impulse control, working
memory, and executive function
Behavioural effects of GABA Anxiety
Generalized anxiety disorder, social anxiety disorder, panic disorder, posttraumatic stress disorder
GABA agonists and positive allosteric modulators are
anxiolytic
Possible models of anxiety - Anxiety is caused by secretion of
endogenous inverse agonists of GABAR →
inhibition of GABAR increases anxiety?
Possible models of anxiety - Ligand activity at
GABAR is shifted in anxiety (subunit alterations?)
Possible models of anxiety - Secretion of
endogenous agonists of benzodiazepine site during stressful
conditions → deficit in anxiety disorders
Behavioural effects of GABA Development
High levels of GABA and developmental changes in GABA
activity (excitatory / inhibitory switch)
Development GABA may contribute to
cell proliferation, survival, and motility
Development Excitatory / Inhibitory balance is important in
normal brain
development
- Excitatory / Inhibitory balance is affected in conditions such as
Down’s syndrome and Autism
Behavioural effects of GABA 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
Behavioural effects of GABA Psychiatric disorders
GABA has been implicated or suggested to play a role in numerous
neuropsychiatric & neurodegenerative disorders
sychiatric 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
Behavioural effects of GABA
* Psychiatric disorders Generally proposed to contribute to
hyperactivity through decreased
inhibitory signalling
