Glutamate and GABA Flashcards
GABA
GABA is the chief inhibitory neurotransmitter in the brain.
- Reduces excitability of cells;
Glutamate
Glutamate is the main excitatory neurotransmitter in the
brain.
- Is present in more synapses than any other neurotransmitter
(that we know of)
Glutamate is synthesized from the
the conditionally
essential amino acid glutamine.
Glutamine can be manufactured in
the body
Glutamine is involved in … detoxification
ammonia
Neurons can transform glutamine into glutamate
using an enzyme called
glutaminase
Once synthesized, glutamate is packaged into…. by …
Once synthesized, glutamate is packaged into
vesicles by three different proteins
VGLUT1, VGLUT2 & VGLUT3;
- Together, these proteins are called vesicular
glutamate transporters (VGLUT)
In order to identify glutamatergic neurons, we look
for
VGLUT
Glutamate, like other neurotransmitters, is released
following a rise in
intracellular Ca2+ levels
Following release, glutamate is rapidly taken back into the
presynaptic cell by a family of five different transporter
proteins:
excitatory amino acid transporters (EAATs)
- EAAT1 5, each with different cellular localizations;
- Astrocytes (EAAT1,2) take up more glutamate than do neurons;
- Major neuronal glutamate transporter is EAAT3;
- EAAT4 are common on Purkinje cells
After astrocytes have taken up glutamate, they convert a major portion of it back to glutamine via
glutamine synthetase
Once released into the synaptic cleft,
glutamate has threecionotropic post-synaptic
receptors to bind to:
- AMPA receptors inward, fast current;
- NMDA receptors inward, slow current;
- Kainate receptors inward, fast current.
All 3 ionotropic post-synaptic
receptors allow Na+ entry into the cell, and therefore cause
depolarization and excitatory
postsynaptic responses
Arguably the most important
physiological function mediated
by glutamate is
synaptic plasticity
- Changes in the strength of
synaptic connections between
2+ neurons;
- Learning & memory;
- Long-term potentiation (LTP);
- Implicated in chronic drug use,
addiction, withdrawal, etc.;
Kainate receptors, likewise, are ionotropic receptors
permeable to
Na+ and can depolarize a cell.
Both AMPA and Kainate (and NMDA) receptors are
comprised of four subunits that come together to form a
receptor channel
(NMDA) receptors
are distinct from AMPA and Kainate receptor
subtypes in several ways
- Permeable to Ca2+ and Na+, and can therefore
trigger Ca2+ dependent 2nd messenger systems; - Opening of NMDA requires a co-agonist in
addition to glutamate (glycine or D-serine); - NMDA receptors possess a binding site for Mg2+
within the ion pore;
- Mg2+ block must be expelled by change in polarity before
NMDA receptor pore can open. - NMDA receptors also possess binding sites for
PCP, ketamine, memantine, MK-801, alcohol,
benzodiazepines, barbiturates, etc
NMDA is a coincidence detector
only activates when
two
events occur close together in
time.
1. Glutamate released onto NMDA;
2. Cell membrane is depolarized
n addition to the 3 ionotropic receptors, glutamate
also has ….. metabotropic receptors
8
Long-term potentiation is mediated by activity of the
NMDA receptors
Long-term potentiation (LTP) is defined as
- A persistent (>1 hour) increase in synaptic strength produced by a burst of
activity in the presynaptic neuron; - Initiated by a burst of firing activity (100 stimuli in ~1s) called tetanus;
- Synaptic enhancements produced by the tetanus is measured in EPSPs on
the post-synaptic cell;
There are many varieties of LTP
- Time period of potentiation (E- vs. L-LTP);
- Pre-synaptic vs. post-synaptic;
- Structural vs. biochemical modifications (or both);
- Underlying cellular mechanism.
LTP occurs in many brain regions but was
first discovered in the
hippocampus
The hippocampus is divided into three
principle pathways:
- Perforant path: entorhinal cortex granule
cells; - Mossy fibers: granule cells pyramidal cells
in CA3; - Schaffer collateral: CA3 CA1 (main
pathway in LTP
Glutamate binds to both …….receptor
AMPA & NMDA
Once Ca2+ enters the cell via NMDA
receptors, it alters the postsynaptic
neuron by:
- Increasing responsiveness of AMPA
receptors to glutamate (how?); - Increase the number of AMPA receptors
expressed on the post-synaptic
membrane; - Triggers the release of retrograde
messengers that cause more glutamate
to be released from presynaptic neuron.
Blocking NMDA receptors, particularly in the hippocampus, can interrupt the
formation of
spatial memories
Excitotoxicity can occur with overexposure to glutamate
caused by a prolonged depolarization of the
postsynaptic neuron
When both NMDA and non-NMDA receptors are
subjected to prolonged stimulation by glutamate,
a large % of cells die via 1 of 2 mechanisms:
necrosis and apoptosis
necrosis and apoptosis
- Necrosis: characterized by rapid lysis of the cell due
to osmotic swelling; - Apoptosis: delayed cascade of biochemical events
that leads to DNA breakup and ultimately cell death
GABA is synthesized in
GABAergic
neurons,
GABA is made from glutamate, a reaction
that is catalyzed by the enzyme
glutamic
acid decarboxylase (GAD).
The vitamin B6 derivative pyridoxal
phosphate is a cofactor in the synthesis of
GABA
Labeling of GAD in presynaptic nerve terminals shows us that GABA synthesis is localized with
mitochondria
Following synthesis in the nerve terminals,
GABA is stored in vesicles via
vesicular GABA
transporters (VGAT)
VGATs are also capable of transporting glycine
into vesicles and are therefore also known as
vesicular inhibitory amino acid
transporters (VIAAT)
GABA is removed from the synaptic cleft
by three different transporters:
GAT-
1, GAT-2 & GAT-3
Once recycled, GABA is then metabolized
back to glutamate and succinate by
GABA aminotransferase (GABA-T
The best characterized binding site is the
benzodiazepine
site (BzR
Prototypical GABAA receptors are:
Selectively activated by muscimol:
- Found in Fly Agaric mushrooms (and others);
- Eaten for its stimulatory and hallucinogenic effects.
Antagonized competitively by bicuculline:
- Blocks binding of GABA to GABAA;
- Potent convulsant.
Antagonized non-competitively by picrotoxin.
- Acts as a stimulant and convulsant;
- Can cause respiratory paralysis.
Because the GABAA receptor has
multiple binding sites, the activity at
the receptor can be exacerbated by
multiple ligands binding
The action of alcohol,
benzodiazepines (BDZs) and
barbiturates potentiate the effects
of
GABA on the GABAA receptor
Barbiturates:
- E.g. Pentobarbital;
- Increase the mean duration of opening time;
- Increase the mean number of openings per burs
Benzodiazepines
- E.g. Valium
- Increase the open frequency of GABAA (BDZ agonis
Picrotoxin
- Does not directly interact with binding site for
barbiturates, but produces the opposite effects on the
receptor; - Reduces the mean number of openings per burst;
- Shortens the mean opening time;
Barbiturates are a unique ligand for the
GABAA receptor, as they exhibit three
modes of action, depending on the
concentration
- At low concentrations, barbiturates act
allosterically on the GABA-gated Cl-
influx co-agonist; - At higher concentrations, barbiturates
open GABAA receptor channel directly,
independent of the presence of GABA
agonist; - At very high concentrations, barbiturates
block the Cl- current antagonis
