Glutamate Flashcards
How is glutamate synthesized?
Since glutamate cannot cross the blood brain barrier, it is synthesized locally, either from glucose from the krebs cycle or from glial cell synthesized glutamine.
Describe the glutamate production cycle?
Glutamine synthesized form glutamate in the glial cells. It is released an taken in the pre-synaptic terminal where it is converted to glutamate by an enzyme called glutaminase. After that, it is packaged into vesicles by VGLUT (vesicular glutamate transporter). It is then released into the synaptic cleft, where excess is taken up by excitatory amino acid transporter (EAAT) and brought into the glial cell where it is broken down into glutamine.
It is also possible for glutamate to go directly from the the cleft back into the axon terminal
What is the name of the transporter that packages glutamate into vesicles?
VGLUT or vesicular glutamate transporter.
What is the name of the transporter that clears glutamate form the synaptic cleft?
It is called EAAT (excitatory amino acid transporter). It takes the glutamate and brings it to the glial cell for recycling.
How is the pH grandient established in the vesicles to power their filing? How it the vesicle then filled?
Vacuolar ATPase. It is filled by an antiporter that exchanges H+ for glutamate
How are glial cells part of the signaling of glutamate?
They have glutamate receptors
Name the glutamate ionotropic receptors.
AMPA, NMDA, KAINATE. Each named for the agoniststhat activate them. They are all non-specific cation channels
Most central synapses contain both AMPA and NMDA receptors.
AMPA causes a big/fast EPSC. NMDA causes a slower and longer EPSC
How many subunits make up the AMPA receptor?
4 Tetrameric. The other receptors have 5 (pentameric) subunits (two of which have to be alpha subunits, so that they have the necessary receptor binding sites).
It has four transmembrane subunits with 2 clam shells coming off of it. Glutamate binds to the inner clamshell and changes the confirmation of the pore and allows for ligand binding at the M2 region. Moreover the M2 loop is the selectivity filter.
The competitive antagonists block the clamshell conformational change by binding to the same spot as the glutamate would have and blocks the pore conformational change.
What is the primary mediator of excitatory responses in the brain?
AMPA because EPSCs produced by AMAP receptors are usually much larger than those produced by other excitatory synapses. In contrast, EPSCs produced by NMDA receptors are slower and last longer.
What is the role of Kainate?
It is less well-defined. In some cases kinate receptors are found of presynaptic terminal and serve as feedback mechansims to regulate glutamate release. When it is found on on the post-synaptic cell, the current rises quickly, and it decays more slowly than the current generated by AMPA.
What is unique about NMDA synapses?
It’s pore allows entry of Ca in addition to Na and K
Another important property of NMDA receptors is that Mg ions block the pore at hyper polarized membrane potentials. Depolarization pushed the Mg ion out of place.
Moreover, NMDA receptors don’t operate unless there is both glutamate and a post-synatic depoalarization to open the pore. The requirement for this coincidence is thought to underlie much of synaptic plasticity.
Another usual feature is that gating of the NMDA pore reqires a co-agonist glycine
What the three things that must happen simultaneously for NMDA receptor to open?
- ) Depolarization to remove the Mg
- ) Glycine must bind
- ) Glutamate must bind
This unique structure allows them to serve as coincidence detectors.
What does APV do?
It blocks NMDA channels
Where does the NMDA receptor have the most significant impact?
On the late current, because there isn’t sufficient depolarization on the early current for the Mg to be popped out.
How do are the glutamate receptors kept opposite the release site?
In the post synaptic density, there is a scaffold that holds the proteins in place. The first discovered was PSD-96 (post-synaptic density of 95 kD). These proteins have PDZ domains that anchor glutamate receptor proteins in place.
PDZ domains bind directly to NMDA receptors, but they are bound by a protein called TARPS (transmembrane AMPA receptor regulatory proteins) to AMPA receptors. These TARPS also play a role in regulating ion flow through the channel.
Mouse mutants lacking TARPS, have misplaced AMPA receptors and develop ataxia (loss of control of bodily movements)
Maintaining this arrangement is very important for neurosystem functionality.
