Glutamate Flashcards
What is the function of glutamate?
It serves as a neurotransmitter
It is a component of many proteins and has other metabolic roles (but we will focus on its role as an excitatory NT)
Because glutamate is found throughout the brain, it is more difficult to assign specific functional roles to this neurotransmitter
What projection neurons use glutamate?
All pyramidal cells in cerebral cortex
hippocampus, amygdala, thalamus. (limbic system)
Glutamate projection neurons embedded in other subcortical nuclei
How do other neurotransmitters interact with glutamate?
To varying degrees, most other ‘classical’ neurotransmitters modulate effects of glutamate on neural activity
Noradrenaline, serotonin, acetylcholine, etc. usually serve to modulate glutamate activity rather than directly affecting neuron potentials themselves
Glutamate is a form of which amino acid?
Glutamate is ionized form of the amino acid glutamic acid
How is glutamate synthesized? (What reactant/enzyme?)
Synthesized from glutamine by glutaminase.
Why does labeling glutaminase not help us identify which neurons are using glutamate?
While we usually identify neurons that are using a particular NT by labeling the specific enzyme involved in its production, this isn’t useful for glutamate because glutamate is too widely used and many cells express glutaminase despite not necessarily using glutamate.
What are the vesicular transporters associated with glutamate and what do they do? Why might they be of interest to researchers?
Different vesicular transporters move glutamate into synaptic vesicles: VGLUT1, VGLUT2, VGLUT3. Knockout mutation usually fatal.
VGLUT transporters found only in glutamatergic neurons and are thus good markers.
Is VGLUT found only on neurons that use glutamate as a primary NT?
No, it’s also expressed on neurons expressing markers that indciate that they use another neurotransmitter (eg. monoamine NT), which suggests that glutamate can be stored and released as a co-transmitter in addition to the primary NT
Why do we see VGLUT expression in the striatum when the intrinsic medium spiny neurons in that area do not use glutamate as their NT?
VGLUT is found in the TERMINALS of the glutamate-releasing neuron, so the VGLUT expression is coming from neurons that are projecting to and synapsing in the striatum, not the neurons that originate from the striatum
How is glutamate removed from the synapse after release?
After release, glutamate is rapidly removed from synapse by Excitatory Amino Acid Transporters (EAAT1 to EAAT5).
Where are EAAT1, EAAT2 and EAAT3 located?
EAAT1-2 on astrocyte glia (adjacent to the glutamate releasing neuron, rather than on the actual neuron terminal itself)
EAAT3 on presynaptic terminals (eg. the terminal of the glutamate releasing neuron)
Majority of glutamate uptake is done by what? What happens to the glutamate after it gets uptaken?
Majority of glutamate uptake is done by astrocytes that then convert glutamate to glutamine by glutamine synthetase.
Why does glutamate not only get reuptaken, but also converted into glutamine?
Storage of excess glutamate as glutamine may serve to protect brain from excessive excitation
What happens to the glutamine that is being stored in astrocytes (after glutamate is uptaken and converted)?
Glutamine is transported out of astrocytes and back to neurons - it can be transformed back into glutamate and thus recycled
Are metabotropic or ionotropic receptors more common for glutamate?
Ionotropic
What are the three subtypes of ionotropic glutamate receptors? What were they named after?
AMPA- named for the selective agonist (α-Amino-3-hydroxy-5-Methyl-4-isoxazolePropionic Acid)
Kainate-named for the selective agonist kainic acid.
NMDA-named for the agonist N-Methyl-D-Aspartate.
How many subunits are ionotropic receptors composed of?
Four subunit proteins
How do subunits relate to ionotropic receptor subtypes?
The three receptor subtypes have different combinations of subunits, explaining the differences in their pharmacology.
Also, there are subtypes of each subtype (eg. subtypes of NMDA receptor) that are built in different ways using different subunit combinations, causing them to differ in their pharmacology and physical properties.
What are non-NMDA receptors?
AMPA and Kainate receptors (which are both ionotropic glutamate receptors) are often lumped together into non-NMDA receptors
They are more straightforward in their activation - they are activated by molecules of glutamate and open up to allow sodium ions to pass through and depolarize the cell
While some AMPA subtypes allow calcium to flow in along with the sodium ions, this is not the case for all AMPA receptors (so we will generalize and say that non-NMDA receptors usually only allow sodium ions to pass through!)
They are ALWAYS activated when there’s sufficient stimulation by glutamate; though sensitivity to glutamate is tightly regulated and too much stimulation will lead to receptor desensitization
Name and describe a drug we learned in class that acts on both non-NMDA and NMDA receptors
Kynurenic acid: non-selective (‘broad spectrum’) glutamate antagonist for AMPA, Kainate and NMDA receptors
Targets all 3 ionotropic glutamate receptors