Glutamat release from neurons. (QUESTION)

[Singh]

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Hello.

I have been wondering how Glutamate is released by neuron; or more importantly WHAT stimulates the release of glutamat.

Some reseach has shown that NMDA-receptors on pre-synaptic terminals (and not only post-synaptic NMDA-receptors) can modulate release of glutamat from pre-synaptic terminals. But I still cannot find what is responsible for the release of glutamat.

Can anyone help me?
Thanks.

 

[felipe5]

I believe glutamate is released just like any other NT. Glutamate is the one of the primary excitatory neurotransmitters used in the CNS, and its release is triggered by a wave of depolarization that travels down an axon, and once it reaches the terminal, triggers the opening of voltage gated calcium channels. This calcium then leads to a series of events which allow vesicles that have the NT stored in it to "dock" with the pre-synaptic membrane, allowing the glutamate to spill out into the synapse. The NMDA receptors on the pre-synaptic side that you are talking about are probably autoreceptors, meaning that when glutamate binds to these pre-synaptic receptors, this works to inhibit more NT from being released.

 

[Skialta]

I will second Felipe.

 

[DrPharm]

Also, NO (nitric oxide) is believe to stimulate glutamate release.

Action potentials & Ca++ influx stimulates exocytotic release of Glutamate into the synapse. Glutamate then binds to NMDA receptors on the post-synaptic terminals to increase influx of Ca++ that binds to Comodulin which activates/triggers/enhances NO Synthase with breaks down arginine to citrulline and Nitric Oxide. Then, Glumate NO diffuses out of the cell into the synapse and diffuses out and binds to a pre-synap. receptor stimulating guanyl cyclase (NO binds to Fe portion of GC) converting GTP to cGMP resulting in glutamate synthesis-->more stimulation * increase sensitivity.

This is part of Long Term Potentiation and often called Retrograde messenging.

We're currently learning ANS in A&P in PharmD school. I'm also planning to apply to MD school afterwards because I'm realizing that I won't get as much satifaction with a PharmD compared to MD. I would appreciate any advice!

 

[Singh]

Thanks for all the answers.

It seems reasonable that glutamate release is triggered by a simple action potential. However, it is also known that cerebral ischemia causes an increased release of glutamate, which opens calcium channels initiating a pathological influx of calcium provoking cell damage. In this way increased levels of glutamate in the brain ECF reflects neurotoxicity.

Any ideas of why ischemia causes release of glutamate? Could it be a stress-reaction? Or does the lack of ATP caused by ischemia have any effect on glutamate release?

Best regards, Singh

 

[TTSD]

isn't there also some retrograde stimulation going on as well?

 

[DrPharm]

isn't there also some retrograde stimulation going on as well?

Yes there is with Nitric Oxide as explained above.

 

[TTSD]

Yes there is with Nitric Oxide as explained above.

Shucks, see what happens when one doesn't read? Now let's talk about up and down regulations along the spine! Amplification! All the good stuff that I learned a year ago but don't remember jack crap about. PK what?

 

[Skialta]

I believe the reason that ischemia causes the release is due to loss of the Na/K pump so that you get general depolarization.

 

[trauma_junky]

Also, NO (nitric oxide) is believe to stimulate glutamate release.

Action potentials & Ca++ influx stimulates exocytotic release of Glutamate into the synapse. Glutamate then binds to NMDA receptors on the post-synaptic terminals to increase influx of Ca++ that binds to Comodulin which activates/triggers/enhances NO Synthase with breaks down arginine to citrulline and Nitric Oxide. Then, Glumate NO diffuses out of the cell into the synapse and diffuses out and binds to a pre-synap. receptor stimulating guanyl cyclase (NO binds to Fe portion of GC) converting GTP to cGMP resulting in glutamate synthesis-->more stimulation * increase sensitivity.

This is part of Long Term Potentiation and often called Retrograde messenging.

We're currently learning ANS in A&P in PharmD school. I'm also planning to apply to MD school afterwards because I'm realizing that I won't get as much satifaction with a PharmD compared to MD. I would appreciate any advice!

Just to add a couple of points, I have my masters in Neruobiology. The primary glutaminergic receptor is the AMPA receptor. The ratio of AMPA to NMDA receptors on the postsynaptic cell is grossly skewed. With high frequency stimulation the AMPA receptors are open longer alowing the postsynaptic [Ca2+] to greatly increase. This causes the insertion of more NMDA receptors into the membrane via the Golgi and allows for easier stimulation and thus LPT (Long term potentiation.) Excess glutamate in the synapse is taken up by adjacent glial cells and metabolized to Glutamine and then exocytosed. The neuron then takes this back up to synth Glutamate again via glutaminase.

 

[trauma_junky]

I believe the reason that ischemia causes the release is due to loss of the Na/K pump so that you get general depolarization.

As far as I know, Ischemia does not cause the release of excitatory NTs but infarction does due simply to the deleterious nature of necrosis in cell death. This leads to the excitatory cascade of events spreading the infarction far beyond the borders of its ischemic origin. There is a study out showing that a 2.0 G IV push of Mag Sulfate significantly decreased the aplification of CVAs.

I know the spelling super sucks tonight, but its 4:40 in the AM.

 

[Skialta]

I had a neurosurg lecture this past week and he basically said whether it is hemorrhage or ischemia producing edema or associated hemorrhage there is the whole cascade of "secondary injury" with tissue injury and ischemia causing the release of glutamate, aspartate, potassium, and intraneuronal Ca.

 

[Singh]

Dear Skialta.

So what you are basically saying is that an insult to the brain (intracerebral hemorrhage, SAH, infarct etc.) will by secondary means cause cerebral ischemia. Sounds very reasonable to me. Did your lecturer mention anything about mechanisms behind this secondary injury?

 

[Skialta]

Not specifically, he did say that it is an area of research right know. I guess there is a general feeling that the secondary effects in many cases are more harmful to the patient than the original insult.

I will say I finished neurosciences yesterday, longest organ system of the year, HOORAAY!


MS2

 

[felipe5]

Dear Skialta.

So what you are basically saying is that an insult to the brain (intracerebral hemorrhage, SAH, infarct etc.) will by secondary means cause cerebral ischemia. Sounds very reasonable to me. Did your lecturer mention anything about mechanisms behind this secondary injury?

perhaps it has to do with microvascular damage, which could be due to various factors such as endothelial damage (and thus less NO synthesis and heavy release of ET-1), along with the activation/adherence of leukocytes to post-capillary venules (increases in vascular permeability). None the less, it don't sound too pretty