Glutamate Flashcards
What are non-essential amino acids?
- Not required in diet
- Synthesized in most cells of the body
What unites all amino acid neurotransmitters?
They all have two functional groups
What are the excitatory neurotransmitters?
- Glutamate, Aspartate, Cysteate, Homocysteate
What are the inhibitory neurotransmitters?
- γ-aminobutyric acid (GABA), Glycine, Taurine, Alanine
Describe aspartate
- Released in a Ca2+-dependent manner
- May not be stored in secretory vesicles
- May be directly released from cell cytoplasm
- Not considered a ‘classic’ neurotransmitter
- Acts at glutamatergic receptors
- Physiological functions unclear
Describe glutamate
- Most widely used excitatory neurotransmitter
- ~90% of all neurons, 80-90% of all synapses are
glutamatergic - Mediates fast excitatory neurotransmission
- Sensory, motor coordination, emotion, cognition, memory formation and retrieval
- Proteinogenic amino acid
- Abundant throughout the cell
- Concentrated in presynaptic compartments
What is glutamate synthesized from?
Glutamine
Describe how this synthesis occurs
In the CNS the majority of glutamate is recycled from glutamine by the enzyme glutaminase
Describe glutamate transporters
- Glutamate is abundant throughout the cell
- Neurotransmitter glutamate is packaged into
vesicles to maintain a separate ‘pool’ of NT - Vesicular glutamate transporter (VGLUT) can be used to identify glutamatergic neurons
- Family of 3 transporters
- VGLUTs are structurally and functionally similar to VMAT
Where are VGLUT family members expressed?
- VGLUT1 and 2 are expressed on distinct glutamatergic populations in the CNS.
- VGLUT3 is expressed in various neurons including GABAergic, cholinergic, and monoaminergic neurons suggesting possible modulatory functions.
What is glutamate metabolized to?
Glutamine
What is the enzyme responsible for conversion of glutamate to glutamine?
Glutamine synthetase
What is responsible for re-uptake?
excitatory amino acid transporters (EAATs)
Describe EAATs
- Glutamate transporters on the cell membrane are termed excitatory amino acid transporters (EAATs)
- Non-specific for both glutamate and aspartate
- Family of 5 transporters (EAAT1- 5)
- EAAT1 and 2 are expressed on astrocytes
- EAAT3 and 4 are expressed on neurons
- EAAT5 is expressed in the retina
- EAAT expression compartmentalizes glutamate recycling
Describe glia in the CNS
- Neurons comprise only 50% of the cells in the CNS.
- The remaining 50% of cells are termed glia (latin for glue).
- Astrocytes – define the brain side of the BBB
- Oligodendrocytes – myelinate axons in white
matter - Ependymal cells – generate and regulate CSF
- Microglia – immune surveillance and development
What are the functions of astrocytes?
- Define the blood brain barrier
- Regulate intake of nutrients and O2
- Regulate blood flow in the brain
- Form extensive signalling networks
- Coupled with electrical synapses – Gap junctions
- Regulate synaptic functions and contribute to plasticity
Describe astrocytes and cognition
- Human astrocytes show dramatic difference from rodent
- Some consider the ratio of glia to neurons a species marker of intelligence
- Proposed to contribute to cognitive processes
- Grafting human astrocytes into mouse cortex increases cognitive measures
Describe the functional effects of EAATs
- High levels of extracellular glutamate are toxic to neurons
- Genetic knockdown of EAAT 1 and 2 (astrocytic) result in widespread increases in glutamate levels esp. in the striatum
- Knockdown of activity of EAAT3 (neuronal type) has much more limited effects
- Astrocyte pathway of glutamate recycling is the dominant pathway
- EAAT2 abnormalities are observed in amyotrophic lateral sclerosis (ALS)
Describe the tripartite synapse
- Glutamatergic synapses are wrapped by
astrocyte processes expressing EAAT1/2. - Glutamate uptake into astrocytes is rapid, high efficiency, and prevents spillover of glutamate into adjacent synapses.
- Astrocytes are the principal site of glutamate breakdown.
- Glutamine is exported from astrocytes and taken up into neurons to be converted back to glutamate.
Describe MSG
- MSG can be used experimentally to induce glutamatergic lesions
- MSG is proposed as one of the five basic tastes (referred to as umami)
- Acts on glutamate receptors on the tongue
- MSG syndrome is a widely reported reaction to MSG
Sodium glutamate (aka monosodium glutamate, MSG)
Describe pyramidal neurons
Projections to striatum, thalamus,
limbic, brainstem
Describe corticospinal tracts
Voluntary motor control
Describe Parallel fibers of cerebellum
Excitatory inputs to Purkinje cells
What is another glutamatergic system?
The hippocampus
What is the agonist of AMPA receptors?
The synthetic AA AMPA
What is the channel type of AMPA receptors?
Non-selective cation channel (accepts both Na and K)
What are the AMPA receptor subunits?
GluR1-4
Describe the composition of AMPA receptors
Heterotetramers aka dimers of dimers
Describe AMPA receptor kinetics
- Rapid kinetics
- Onset, offset, desensitization occur within
milliseconds - Single channel conductance on picosecond
timescale (10-12 s)
Describe AMPA antagonists
Experimental antagonists: NBQX, CNQX, DNQX
What mutations impact AMPAR?
- Specific mutations in AMPAR (GRIN2A gene)
associated with 58% decrease in Parkinson’s
risk if also a heavy coffee drinker
What is the agonist of kainate receptors?
Kainate
What are kainite receptor subunits?
GluK1-5
Describe kainate receptor kinetics
Slower than AMPAR
What is the antagonist of kainate receptors?
NS102
What is the function of kainate receptors
- Limited role in fast, excitatory
transmission - Can be expressed presynaptically at GABAergic synapses
Agonists cause seizures (same for AMPA)
What are the endogenous agonists of NMDA receptors?
Glutamate & glycine
What are the exogenous agonists of NMDA receptors?
NMDA → synthetic AA
What type of channel do NMDA receptors have?
Non-selective cation channel (accepts both Na, K & Ca2+)
Describe the glutamate binding site
obligatory agonist binding site
Describe the glycine binding site
obligatory co-agonist binding site
Describe polyamine binding site
Site of endogenous allosteric
modulation (positive)
Describe the magnesium binding site
voltage dependent block of channel
opening
Describe the zinc binding site
negative allosteric modulation site
Describe the hydrogen binding site
pH sensitive negative modulation
Describe what makes NMDA unique
Co-expressed with either AMPAR or kainate
Describe NMDAR kinetics
Under normal resting state
conditions Mg2+ occupies the
channel pore.
Agonist binding alone is insufficient
to allow ion flux.
The pore is ‘unblocked’ when a
depolarization is previously present
– displacing Mg2+ in an voltage-
dependent manner.
NMDA receptors are only active
after an initial depolarization
(through AMPA receptors).
NMDA is described as a
coincidence detector – opening
only under conditions of strong or
repeated stimulation.
Describe endogenous NMDAR antagonists
Zinc (allosteric) and Mg
Describe exogenous NMDAR antagonists
noncomp MK801, noncomp PCP and Ketamine
What is the function of NMDA receptors?
Important in learning and
memory processes by
modulating synaptic strength
