The 12th Invest in ME Research Conference June, 2017, Part 2
MEMum presents the second article in a series of three about the recent 12th Invest In ME International Conference (IIMEC12) in London.
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What is the Biological Reason for Having Different Receptor Subtypes (eg: Dopamine D1, D2, D3, etc)?

Discussion in 'General ME/CFS Discussion' started by Hip, Sep 22, 2015.

  1. Hip

    Hip Senior Member

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    Neurotransmitter receptors come in variety of different subtypes: for example, the receptor for dopamine has 5 different subtypes (the dopamine receptor D1, D2, D3, D4 and D5); and the receptor for serotonin has 14 different known subtypes (5-HT1a, 5-HT1b, 5-HT2a, 5-HT2b, 5-HT3, 5-HT4, etc).

    Each receptor subtype is often located in specific parts of the brain. This is actually very useful from the pharmacological point of view, since drugs can be developed which target and act upon specific receptor subtypes in specific areas of the brain, and in that way, you can develop drugs that operate in particular brain regions.

    Here for example is the distribution of the
    various
    dopamine receptor subtypes in the brain
    :
    Dopamine receptor distribution in brain.png
    Source: Distribution of dopamine D1–D5 receptors in normal brain

    However, as far as I am aware, this selective targeting of receptor subtypes does not actual occur in normal human biology: each human neurotransmitter will activate all the subtypes of its receptor. For example, the neurotransmitter dopamine will activate each of the 5 dopamine receptors.



    So my questions is:

    What is the biological purpose for having different neurotransmitter receptor subtypes?

    As far as I am aware, normal biology does not make use of the actual differences in these receptor subtypes, so why are these differences there?

    Certainly they are very handy from the perspective of creating drugs that target specific brain regions. But what use does nature make of the differences in these receptor subtypes?

    Are these different receptor subtypes (which are each represented by the own gene) just there as a random (but pharmacologically fortunate) evolutionary accident?

    @Jonathan Edwards, perhaps you will know the answer to this question.
     
    Last edited: Sep 22, 2015
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  2. adreno

    adreno PR activist

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    The activation of the different subtypes have different effects, for example D2 is an autoreceptor, activation of which will lower the amount of neurotransmitter released. So having this kind of variation is still useful from a biological perspective. It's what happens after the activation of the different subtypes that is interesting in this context.
     
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  3. alex3619

    alex3619 Senior Member

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    To add to what @adreno said, each receptor subtype can be regulated separately. Each is tied to different effects. So it gives cells extra mechanisms to regulate hormone response.

    There are also phantom receptors, though that is not the official name, it escapes me right now. A cell making these can mop up hormone without responding. This happens with cortisol for example. So the cell can ignore tissue or serum hormone levels if it triggers production of these phantom or decoy receptors. Its possible that sIL2r is another one of these, though I am less sure about that as this one might be due to cell death and degradation.
     
  4. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    Just finished reading a forum answer from dr marianco, ssri's serotonin/dopamine /noradrenaline and adrenal fatigue.

    he mentions many af patients have high noradrenaline with low dopamine and cortisol. He mentions getting the right level of serotonin can lower perceived stress and noradrenaline , which then increases dopamine . Too much serotonin signaling he says reduces dopamine , so its about getting it just right.

    abit off the track but he seems big on interrupting noradrenaline signalling to help treat and recover from AF. He does mention hc can interrupt noradrenaline signalling as well as testosterone . For some they require all this to be balanced with possible low dose ssri as a way to treat adrenal fatigue /dysfunction and improve dopamine.

    it seems nothing works in isolation as there as so many balances and checks .

    Maybe its closer to the point to say dopamine fatigue than adrenal fatigue.

    marianco has some interesting theories from his experience as an endocrinologist/psychiatrist .
     
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  5. alex3619

    alex3619 Senior Member

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    Dopamine is coming up more and more in expert discussions. This might get interesting.
     
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  6. Hip

    Hip Senior Member

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    I appreciate that each receptor subtype can be tied to specific effects; that is because receptor subtypes are often located in particular functional regions of the brain, and so a given receptor subtype will be linked to the function of its brain region.

    However, I can't see how each receptor subtype can be regulated separately in normal biology, when all receptor subtypes will respond to their respective neurotransmitter. All dopamine receptor subtypes, for example, will respond to dopamine. If you were to introduce dopamine as a drug into the brain, all the dopamine receptors, D1 to D5, would respond to it.

    By contrast, if you were to take a drug like cabergoline, a dopamine receptor agonist which has high affinity for the dopamine D2 receptor, then you would be selectively activating this D2 receptor with this drug.

    So drugs are capable of selective activation of receptor subtypes, but the body's own neurotransmitters are not. The body cannot use dopamine to selectively activate a specific receptor, because dopamine has good affinity for all subtypes of dopamine receptor (although interestingly I read that dopamine has slightly more affinity for the D2 receptor than the D1).



    Obviously, any dopamine receptor is going to be much more strongly activated by dopamine released in close proximity to that receptor, ie, by dopamine released from an adjacent neuron across the synaptic cleft. So there is localized control of any dopamine receptor in that sense. But that localized control would presumably still work just as well if all the various dopamine receptor subtypes found in the brain were converted into the same subtype (all converted to say subtype D1).

    So then what is the biological purpose of having different receptor subtypes?
     
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  7. alex3619

    alex3619 Senior Member

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    Its not difficult to explain how they are regulated separately. The cell can make more or fewer receptors, and can make decoy receptors. The cell sets the level of response.
     
  8. Hip

    Hip Senior Member

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    But wouldn't that type of regulation, ie changes in receptor population density, work just as well if all the brain's dopamine receptors were changed to subtype D1?

    This is probably the sort of experiment that you could do with gene knock-out type techniques on mice: you could change all the mouse's dopamine receptor genes to a type D1 gene, and see what happens.
     
  9. adreno

    adreno PR activist

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    There's no great mystery here; it's very simple: different receptor subtypes are tied to different effects. For example see this diagram of norepinephrine receptors:

    [​IMG]

    Norepinephrine binds to both alpha-1, alpha-2 and beta receptors, but the effects (reactions) are different. If you only had one receptor subtype this would not be possible. If for example you only had the alpha-1 subtype, only smooth muscle contraction would be possible, and all the other effects in the diagram would be impossible. In short, you'd be dead without receptor subtypes, as most biological functions would be missing.
     
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  10. Hip

    Hip Senior Member

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    It would be possible: if you were to individually replace every single beta receptor in the heart muscle with an alpha receptor, the heart muscle would still function as per normal, as far as I can see.
     
  11. adreno

    adreno PR activist

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    Seriously, Hip? Surely you must be joking. Here is a list (probably not exhaustive) of biological functions that you would be removing by turning alpha-2 and beta receptors into alpha-1 receptors:

    https://en.wikipedia.org/wiki/Adrenergic_receptor
     
  12. Hip

    Hip Senior Member

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    @adreno, you not actually reflecting on what is being said, and so I think you are missing the point. It's not very difficult.
     
  13. adreno

    adreno PR activist

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    I am replying exactly to your posts. You said:

    Which is completely false. You cannot turn all the beta receptors in the heart into alpha receptors and still have it function normally. However, I won't be wasting any more of my time explaining the obvious to you, since your argumentation consists only of me "missing the point".
     
  14. Hip

    Hip Senior Member

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    I think I am not explaining it clearly enough then @adreno. Let my try again:

    Since an alpha receptor responds in exactly the same way to norepinephrine as a beta receptor, if you were to put an alpha receptor in the place of every beta receptor, nothing would change.

    When the beta receptor is activated by norepinephrine, that receptor conveys a message into the cell that then activates the cellular functionality linked to that beta receptor.

    If you were to replace that beta receptor with an alpha receptor, ie, "pull out" the beta receptor from the cellular membrane and insert an alpha receptor in its exact place, then when that alpha receptor was activated by norepinephrine, it would convey the same message into the cell that then activates the same cellular functionality (the cellular functionality that was previously linked to the beta receptor) .

    So nothing changes, as far as I can see.
     
  15. adreno

    adreno PR activist

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    It doesn't respond in the same way as a beta receptor. That's whole point. Otherwise, there wouldn't be differential functions. Different receptor types (and subtypes) respond in different ways. This effect is known as signal transduction:

    https://en.wikipedia.org/wiki/Signal_transduction
     
  16. Hip

    Hip Senior Member

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    Well that's one potential answer to the question that had occurred me: that the gene for a receptor also encodes for at least some of the signal transduction mechanism.

    But does anyone know for sure whether or not the gene for a receptor encodes some of the signal transduction mechanism?

    For example, the DRD1 gene encodes the dopamine D1 receptor; does the DRD1 gene also encode for some of the mechanism by which the signal from this receptor is conveyed into the cell? And if so, is this mechanism different to that encoded in the DRD1 gene, which encodes the dopamine D2 receptor?

    Dopamine receptors are G protein-coupled receptors, meaning G protein is the mechanism by which the receptor signal in conveyed into the cell. But G proteins have their own genes, so this indicates that much (if not all) of the signal transduction mechanism is not encoded by the dopamine receptor gene.
     
  17. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    I do not know about these particular receptors but adreno and alex are making good sense here. I think you are missing the implications, hip. If you take IgG Fc receptors there are three families, with several variants within each - maybe ten receptors in all. Each has a different gene or splice variant origin which determines the affinity and range of specificity of the receptor, the signalling tail - which can be positive, negative or null and through different kinases linking to different pathways, the rate of replacement if ligated, how the receptor sits in the membrane and what it associates with and countless other things. Each gene has a promoter that is responsive to different transcription factors that switch it on in different types of cells under different conditions. And there is lots more detail. In the 1980s we had no conception of this sort of complexity and it is expanding all the time. having one sort of screwdriver does not mean you have to just have one sort of screw - you may want dozens of different sorts for different jobs.
     
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  18. Hip

    Hip Senior Member

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    The gene expression angle makes sense as to why there may need to be different genes for receptor subtypes: because the body might want to promote or inhibit the expression of one subset of receptors, but not another subset. And I can appreciate that the same receptor class expressed in different locations may conceivably need to have different signaling tails, hence the need for different receptor subtype genes.



    However, my question is really more about the ligand end of the receptor, rather than differences in the signal transduction end. Perhaps I should have made this clearer in my original post. I don't think I am explaining myself very well.

    What I am trying to understand why the body has this setup such that various exogenous ligands (eg, drugs) have different binding affinities for different subtypes of the same class of receptor, which presumably means that the protein structure of the ligand end of the receptor is different across receptor subtypes.

    As far as I am aware, there is only one endogenous ligand for a given neural receptor class: dopamine is the endogenous ligand for the dopamine receptor and all its subtypes, serotonin is the endogenous ligand for all serotonin receptor subtypes, GABA is the endogenous ligand for all GABA receptor subtypes, and so forth.

    So I don't understand why the ligand end of the receptor is not exactly the same for all the subtypes of a receptor. Unless these neuronal receptors are also acted upon by other secondary endogenous ligands that I am unaware of (or science is unaware of).

    In short: the ligands are always the same: dopamine is always dopamine, serotonin always serotonin; so if the ligands are identical, why isn't the ligand end of the receptor also identical across subtypes (even if the signaling tail of the receptor is different)?

    Maybe there is a good reason why it varies.
     
  19. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    It is a reasonable question but I think we understand the answer. When the genome mutates to generate new genes it does so by random changes both to protein structure and to transcriptional regulation sites. A common situation is for a single gene for a receptor to be duplicated, probably by a simple translocational one gene frame shift during meiosis. The offspring then has two copies of the same gene side by side in their DNA. These genes will immediately start to drift in terms of the protein structure they encode. One copy is likely to stay the same to maintain a needed function but the other copy may mutate to a slightly different version with a slightly different ligand peptide sequence. The reasons why this may then gradually become established as a new receptor with usefully different transcription regulation rules are complex but it worth remembering that this sort of random structural wandering about is the ONLY way we can acquire new useful genes.

    In addition to this there may actually be some significance to the different repertoires of binding for 'non-physiological' ligands. Note that most neurotransmitter receptor agonists and antagonists are plant alkaloids like atropine or curare or ergotamine. There may be important advantages in structural drift in ligand peptide sequences over a long period of evolution - even if there may be disadvantages as well. Plants are constantly adapting to survival by changing their alkaloids to best poison animals that eat them. Animals will be constantly adapting their neurotransmitter receptors to avoid binding the alkaloids. If the animal has three genes for X receptors to be used in different contexts, each gene is going to drift a different way towards its receptor avoiding binding alkaloids.
     
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  20. Hip

    Hip Senior Member

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    @Jonathan Edwards
    That's a great explanation of one factor that may force neurotransmitter receptor genes to start drifting: the need to avoid the toxic effects of plant alkaloids, which are part of a plant's defense.


    I saw a documentary once about the evolutionary arms race between venomous snakes and their prey. They said the prey's immune system is rapidly evolving to try to better deactivate the venom, and the snake venom genetics are also rapidly evolving to try to maintain the venom's toxicity again the prey. Apparently some anti-venom drugs created several decades ago are now losing their effect, due to this arms race and the rapid genetic drift of the snake venom.
     

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