The Clinical Significance Of G-Coupled Receptors, Neural Mapping and the Future of Rx

[airsh0w]

I have just learned a bit about G-coupled receptors from videos, Wikipedia, and the Erowid/BL textbook project and I am curious how this knowledge of these cascades has bettered pharmacology. I understand it is a pretty new development with the G-Protein being discovered in in 1994, just about 18 years ago.

Has there been breakthroughs using this knowledge? Any drugs that specifically owe themselves to this new field of knowledge or has it not gotten to that point? I can really see how much potential these cascades could bring to selective and efficacious drug development especially when they are mapped out and there functions better understood.

I would love to see a neural map of the brain with the different regions, receptor types, subtypes and neural networks. If anyone wants to do that and needs an intern I'm down but it must be difficult or is it in the works?

I could see (as a layman but I suspect I'm wrong) neural mapping getting done with repeated somewhat harmless radioactive ligands (PET scans) overlaying
several prototypical or probabilistic specialized regions if the genetic data is not yet in. But that's just my extrapolation but I think that neural mapping is essential. Then with some research in plasticity we can predict neural "rewirings" and create a computer database machine to create custom drugs based on genetics and people could be scanned for experiential changes in neural anatomy and then overlay a personalized receptor neural network map and list all possible drug remedies including theoretical experimental choices which the person could choose to be a sponsor of testing and if enough sponsors are there then the new theoretical drugs could get created in a democratic process and as the pharmacological-theory gets better the computer will get better at calculating potential drugs and no testing will be needed and everyone will get individual drugs fit to all their genetic, physiological, experiential and subjective personal needs. But is that the end? Cheap, personalized, selective drugs? That is perhaps the end of drugs but drugs could altogether be replaced by in vivo genetic therapy to alter genes to whatever one desires which will finally reach our initiative of eliminating undesired suffering and sadistic pleasure for the most part. But I could see drugs re-emerging in some futuristic psychonauts looking to mess around.
g
But perhaps a am a bit of a bio-psychological Utopian. It could turn out pretty horrible too with mind control drugs or something ridiculous like that.

 

[Epsilon Alpha]

I haven't seen much on neural effects of G-protein specific drugs yet but I'd be shocked if we didn't see something new on this in the next 5 or 10 years.

One potential issue is that there isn't much specificity for Galpha or Gbetagamma, though they might find something to address that. For example, you'd run into issues you get with non-selective drugs random ass effects all over the body due to the real lack in diversity for GPCR signalling.

 

[skillet]

The trouble with blocking G-protein (or further downstream) signalling is that several receptors typically signal through a particular G-protein, eg., from wiki, Gi couples to:

Acetylcholine M2 & M4 receptors
Adenosine A1 & A3 receptors
Adrenergic α2A, α2B, & α2C receptors
Apelin receptors
Calcium-sensing receptor
Chemokine CXCR4 receptor
Dopamine D2, D3, D4
GABAB receptor
Glutamate mGluR2, mGluR3, mGluR4, mGluR6, mGluR7, & mGluR8 receptors
Histamine H3 & H4 receptors
Melatonin MT1, MT2, & MT3 receptors
Opioid δ, κ, μ, & nociceptin receptors
Prostaglandin EP1, EP3, FP, & TP receptors
Serotonin 5-HT1 & 5-HT5 receptors

So blocking Gi would be akin to antagonising all of those receptors, excluding the (likely) possibility that some/all of those receptors are also capable of signalling through other G-proteins. So I'd guess the chances of discovering useful drugs that operate like that would be pretty low, though I was just reading that lithium apparently blocks several steps in the PI (Gq coupled) signalling pathway, so you never know...

 

[PsychedelicPeptide]

Some of the dopamine receptor partial agonists in clinical use, such as Abilify- which I heard some guy lecturing about a few months ago, couple selectively to one pathway. From what I took from the lecture, part of the problem in studying these interactions lies in the neuron itself where a lot is going on and it can be easy to miss these sorts of things if you are not looking exactly for it.

Also you can look at the Paul Allen Brain Atlas and find mRNA expression in all parts of the brain. This more or less leads to knowing what proteins are expressed where, but is certainly not the easiest thing to make use of.

 

[airsh0w]

I haven't seen much on neural effects of G-protein specific drugs yet but I'd be shocked if we didn't see something new on this in the next 5 or 10 years.

One potential issue is that there isn't much specificity for Galpha or Gbetagamma, though they might find something to address that. For example, you'd run into issues you get with non-selective drugs random ass effects all over the body due to the real lack in diversity for GPCR signalling.

That is a certain problem but perhaps indirectly this research will lead to new developments.

The trouble with blocking G-protein (or further downstream) signalling is that several receptors typically signal through a particular G-protein, eg., from wiki, Gi couples to:

Acetylcholine M2 & M4 receptors
Adenosine A1 & A3 receptors
Adrenergic α2A, α2B, & α2C receptors
Apelin receptors
Calcium-sensing receptor
Chemokine CXCR4 receptor
Dopamine D2, D3, D4
GABAB receptor
Glutamate mGluR2, mGluR3, mGluR4, mGluR6, mGluR7, & mGluR8 receptors
Histamine H3 & H4 receptors
Melatonin MT1, MT2, & MT3 receptors
Opioid δ, κ, μ, & nociceptin receptors
Prostaglandin EP1, EP3, FP, & TP receptors
Serotonin 5-HT1 & 5-HT5 receptors

So blocking Gi would be akin to antagonising all of those receptors, excluding the (likely) possibility that some/all of those receptors are also capable of signalling through other G-proteins. So I'd guess the chances of discovering useful drugs that operate like that would be pretty low, though I was just reading that lithium apparently blocks several steps in the PI (Gq coupled) signalling pathway, so you never know...

I always wondered how lithium worked and being that it is a +1 Ion I am not surprised it is somewhat toxic but effective mood stabilizer. Since I could see how it could interfere with the NA+,CA+2,CL, K+ ion channels the body works with. I agree with you but I do have a feeling that this research is going to lead to better drugs in one way or another and like you said, "you never know."

Some of the dopamine receptor partial agonists in clinical use, such as Abilify- which I heard some guy lecturing about a few months ago, couple selectively to one pathway. From what I took from the lecture, part of the problem in studying these interactions lies in the neuron itself where a lot is going on and it can be easy to miss these sorts of things if you are not looking exactly for it.

Also you can look at the Paul Allen Brain Atlas and find mRNA expression in all parts of the brain. This more or less leads to knowing what proteins are expressed where, but is certainly not the easiest thing to make use of.

This is the kind of insight I love to hear. G-proteins are what make receptors effects different from each other. Perhaps some receptors have the same effect once activated but different require different conformations to activate them. If anyone has any insight on this it would be appreciated. Do some receptors have the same intracelluar effect but have a different conformation?

 

[Epsilon Alpha]

*mentions the fact that most 5HT2A partial agonists have functional selectivity, stands back and watches minds blow*
But yeah if you mean functional selectivity of signalling pathways then there are a shit tonne of drugs out there, notably the classical psychedelics.

 

[airsh0w]

*mentions the fact that most 5HT2A partial agonists have functional selectivity, stands back and watches minds blow*
But yeah if you mean functional selectivity of signalling pathways then there are a shit tonne of drugs out there, notably the classical psychedelics.

So the psychedelics have G-protein functional selectivity. I appreciate you sharing that. That answered a few other of my questions about NMDA antagonist functional selectivity and 5-HT2a in general.

 

[i are spectre]

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[rollingstoned!]

It would turn out very bad, I guarantee you that.

 

[i are spectre]

there are two basic receptors throughout our body: g-protein and non-g-protein

a g-protein receptor just means that when a ligand (drug/chemical) binds to the receptor, the receptor activates a protein rather than immediately opening an ion channel. this is just basic cell communication and physiology.

g-coupled protein receptor = RECEPTOR THAT CHANGES SOMETHING in layman's terms

that's what the entire field of pharmacology is based on man. "g-coupled protein receptor" is -basically- just a fancy way of saying RECEPTOR. it is what the entire pharmaceutical industry is based upon, RECEPTORS (or g-coupled receptors and ion channels).

take a college biology course or microbiology and it's something you'll learn fairly early on mate.

you might as well ask "DNA was discovered quite a few years back, has any significant research gone into this?"

 

[airsh0w]

there are two basic receptors throughout our body: g-protein and non-g-protein

a g-protein receptor just means that when a ligand (drug/chemical) binds to the receptor, the receptor activates a protein rather than immediately opening an ion channel. this is just basic cell communication and physiology.

g-coupled protein receptor = RECEPTOR THAT CHANGES SOMETHING in layman's terms

that's what the entire field of pharmacology is based on man. "g-coupled protein receptor" is -basically- just a fancy way of saying RECEPTOR. it is what the entire pharmaceutical industry is based upon, RECEPTORS (or g-coupled receptors and ion channels).

take a college biology course or microbiology and it's something you'll learn fairly early on mate.

you might as well ask "DNA was discovered quite a few years back, has any significant research gone into this?"

I was specifically talking about the intracelluar cascades that are very recent discoveries and actually haven't been tapped into much at all as noted in some other posts in this thread. Actually almost nobody mentions them at all in this forum. i.e. cAMP, Kinase...

 

[i are spectre]

cyclic amp and kinases? they're not that recent. i mean they're basic mechanisms in all cells mate, like i said. not only human cells but all types of eukaryotes. electron transport chain, krebs cycle, blah blah. basic cell function bro (that's probably why they're not mentioned).

"the future of rx, basic cell function!"