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Action potentials VS transduction cascades via transmitter/receptor binding?

JohnBoy2000

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So, a neurotransmitter in the synapse binds with a receptor protein on the post synaptic membrane.
Say it's g-protein coupled.

The transduction process I can't list out precisely but, something to the effect of, g-protein activating ion channels, gives rise to kinases activating protein phosphorylation - somewhere in there about transcription factor incorporation into RNA and the resultant biological effects.

However - in the neuropharm books, there were mention of GIRK's by example, ion channels - but it did not seem to stress to what degree the cell hyperpolarization plays a role, or the degree to which it's implicated by the initial post synaptic binding.

I know in the pre-synaptic cell, an action potential generated via binding of transmitter at the dendritic end of the cell, causes the release of the transmitter at the axon terminal.

But in the post synaptic cell?

Cell hyper and depolarization would obviously play a significant role in the flux of ions in and out of the cell, or perhaps the flux of ions determines the cells polarization?

In any case - wouldn't that post synaptic cells polarization, play a significant role in the drug effects?

Obviously - my facts aren't in exact order so - if anyone better versed in this area can clear things up a little here.

Basically - post synaptic cell polarization and how it implicates therapeutic effects of drugs directly?
If that makes sense?
 
The ions play a critical role in the brain and the effects of a drug, but GPCR activation can have both acute and chronic effects on ion flux. Acutely, activation of some GPCRs will trigger ion influx via effects on channels. The ions can then rush down the neuron to the axon to trigger transmitter release (depending on the type of ion influx). Chronically, GPCRs can cause genetic changes that have a slower but more persistent effect on ion influx/efflux (it takes time for the proteins to be incorporated into the cell).

The NMDA receptor is probably a good example here.

Normally a Mg block sits in the channel pore, and only when the post-synaptic cell depolarizes sufficiently does the Mg block release, allowing ion flux at the NMDA receptor. In order for the post-synaptic cell to depolarize, there needs to be sufficient input provided to the post-synaptic cell (from other terminals). This means that many neurons will have to be firing onto the post-synaptic neuron at once in order to depolarize it, and physiologically this can serve as a so called "coincidence detector", in the sense that the inputs are kind of temporally linked.

Once ions flux through the NMDA channel, this can trigger a process like Long Term Potentiation which has both acute and chronic components.
 
It actually eluded me temporarily that ionotropic receptors, are the class which act primarily to flux ions.

In terms of how g protein subunits flux ions - I assume via disassociation, activation of a cascade of some kind and then..... I'm not really sure?
The cascades end result yields proteins that implicate ion channels thus affecting their presence/movement etc?

One or two general questions which I should know but am not clear on:

1) an axon terminal will always fire onto the somatodendritic end of the next neuron?
As in, that's the order?

2) regarding post synaptic cascades, generally speaking - we've got the enzyme/kinase 2nd messenger effect, the protein phosphorylation effect, then something goes on - and genetic expression gets modified, which yields long term potentiation (if my understanding of that is correct), and the therapeutic drug effects.

Any links to, or explanation of, the interim process?

Something something, transcription factors.... is in there I believe.

3) Excitatory transmission.
By example - glutamate being the primary excitatory transmitter.
Excitatory does not refer to stimulating - as would be the case with NE/DA activation.
It refers to - what then?
As in, more profound neuronal cascades?

5ht2a by example, is regarded as the primary excitatory serotonergic receptor subtype - yet it is not regarded as stimulating, can be associated with hallucinogenics.
So then precisely does "excitatory" refer to?

4) I'm also struggling with the "extra neuronal" picture as in - circuitry.
By example - NMDA blockade - a blockade of the primary excitatory transmission mediator - can result in downstream catecholamine release....?
Or inhibitor GABA can paradoxically enhance transmission depending on the region it implicates?
I'm sure something to do with various brain regions, the projection of a neuron from one to the other - but in terms of getting better insights into this - there has to be a relevant text book or paper or source of some kind that can provide this?


I'm obviously piecing together the various elements in an attempt to get a good visual of the entire process.
The above points are the ones that are eluding my at the moment.
 
5) I'll just slot this in quickly also - I believe I may have asked this before but, it's explanation is key in terms of the aforementioned points.

The elevation of synaptic neurotransmitter via certain pre-clinical/experimental therapeutic agents, does not reliably yield consist therapeutic results.
Yet - with clinically approved agents - it does.

If a certain drug blocks a transporter - it's elevating endogenous neurotransmitter.
Regardless of the agent - the endogenous transmitter should yield a cascade, a similar effect.

But - academic papers consistently suggest that - this is not the case.

The reason being?
Something to do with cross over cascades?
Or is this in reference to the use of synthetic agents are direct agonists, vs endogenous transmitters as the agonist - in the latter instance, there should be no variation in activation pattern and therefore, the therapeutic result would reliably come about??

That may sound confusing but - I'm not well versed enough in this material to know how to phrase it better just yet.
 
I've been using wikipedia primarily to get insights into the specific effects of receptor subtypes, g-protein mediated cascades etc.

Is that really the best source to learn about that type of information?
It's organized reasonably well, vs google scholar where on has to troll through link after link?
 
I've been using wikipedia primarily to get insights into the specific effects of receptor subtypes, g-protein mediated cascades etc.

Is that really the best source to learn about that type of information?
It's organized reasonably well, vs google scholar where on has to troll through link after link?

As one of the editors who writes/revises Wikipedia's articles on neurotransmitter receptor proteins, I'd say yes. :p

Personal bias aside, it really depends on the article. I rewrote about half of the article on TAAR1, which is a good example of how receptor proteins should be covered on Wikipedia; however, the main thing that this article is lacking is coverage of the cognitive and behavioral effects of selective TAAR1 activation in humans. The only reason for that omission in this article is that those effects are not yet known. Wikipedia articles on other neurotransmitter receptors are usually good sources of information on receptor ligands, structure, and the corresponding gene, but sometimes fail to adequately cover the tissue distribution of the receptor (i.e., where it's located in the body), the functional effects of receptor activation in the various tissues where it's located, and the clinical significance of the receptor. IMO, a sizable fraction of Wikipedia's articles on receptor proteins inadequately cover the cognitive and behavioral effects of neurotransmitter receptor agonist/antagonism (e.g., DRD1). GPCR oligomers are very often not mentioned at all in Wikipedia articles on G protein-coupled neurotransmitter receptors (e.g., heterodimers like the D1-D2 receptor heterodimer and TAAR1-D2 receptor heterodimer; both of these heterodimers are listed in the articles on those receptors, so they're not good examples of ones that aren't mentioned), but they should be.

In most but not all cases, a better alternative to Wikipedia for comprehensive information on receptor pharmacology is IUPHAR's website and IUPHAR's review articles on neurotransmitter receptor families. When I write or edit an article on a receptor protein, my go-to source is IUPHAR's website, which has a dedicated webpage on every neurotransmitter receptor. Each page on a receptor protein contains a reasonably detailed overview of what is currently known about it. If I'm looking for more comprehensive coverage of a receptor's pharmacology than what they've published on their website, I typically do a pubmed search for the IUPHAR review on the corresponding class of neurotransmitter receptors; those reviews contain a LOT of very detailed/focused/comprehensive information about the class of receptors as a whole as well as each receptor in the class.
To illustrate what I mentioned about IUPHAR, a fairly detailed overview of dopamine receptor D1 (DRD1) pharmacology is contained in IUPHAR's DRD1 webpage, whereas IUPHAR's review on dopamine receptors contains far more information about DRD1 compared to the webpage.

Edit: With respect to coverage of the pharmacology of a receptor ligand, Wikipedia's article on a ligand/compound is almost always a better source of information than IUPHAR's webpage on the ligand (assuming it even exists).
 
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