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T3 intracellular calcium and caffeine

Discussion in 'Other Health News and Research' started by pattismith, Jun 3, 2018.

  1. S-VV

    S-VV Senior Member

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    And:

    The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter (MCU)

    Here, we characterize a mouse model that lacks expression of the recently discovered mitochondrial calcium uniporter (MCU). Mitochondria derived from MCU-/- mice have no apparent capacity to rapidly uptake calcium. While basal metabolism appears unaffected, the skeletal muscle of MCU-/- mice exhibited alterations in the phosphorylation and activity of pyruvate dehydrogenase. In addition, MCU-/- mice exhibited marked impairment in their ability to perform strenuous work
     
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  2. S-VV

    S-VV Senior Member

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    I think this can be related to Navieaux theory of CDR and cells in the early stages limiting the calcium uptake or expression of MCU to switch from oxphos to glycolisis. Maybe forcing a higher concentration of calcium inside the mitochondria got you out of the CDR.

    On the other hand, if someone has mutations in their calcium channels, the intracelular/ intra-mitochondrial Calcium couldn't be restored, and the signaling Cascade to exit CDR could not begin properly. Now where have we seen such mutations...

    Novel identification and characterisation of Transient receptor potential melastatin 3 ion channels on Natural Killer cells and B lymphocytes: effects on cell signalling in Chronic fatigue syndrome/Myalgic encephalomyelitis patients

    TRPM3 surface expression on both NK and B lymphocytes in healthy controls. We also report for the first time, significant reduction in TRPM3 cell surface expression in NK and B lymphocytes, as well as decreased intracellular calcium within specific conditions in CFS/ME patients
     
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  3. Iritu1021

    Iritu1021 Breaking Through The Fog

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    Yes, I think that's what it means. That when you're on lithium more IP3 is available and cytoplasmic Ca gradient goes up - and therefore more calcium is able to enter the mitochondria. And since IP3 is phosphate, it might be part of the reason why calcium phosphate is so effective for me. One might also try adding inositol to the mix.
     
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  4. Iritu1021

    Iritu1021 Breaking Through The Fog

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    @Gingergrrl
    Ionized calcium is a very common test. It's ordered in ER and on hospitalized patients all the time. Your doctor can order it or you can buy it on directlabs. It measures the fraction of calcium in the active form (similar to how free T3 measures the fraction of active thyroid hormone).

    It needs to be done fasting and you would need to be off calcium and vitamin d supplements for a week. Yes, the T3 in Armour might be keeping your calcium up - so you might want to do it off T3 when you're feeling pretty hypothyroid to get the most accurate read.

    I've never heard about these N-type calcium channel antibodies. Do you know if it act similar to a calcium channell blocker or does it act as an agonist on those channels (similar to Grave's antibodies that stimulate the receptor)?
     
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  5. Iritu1021

    Iritu1021 Breaking Through The Fog

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    Very interesting!
     
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  6. Iritu1021

    Iritu1021 Breaking Through The Fog

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  7. Iritu1021

    Iritu1021 Breaking Through The Fog

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    Here's the full mechanism of action. Turns out it's a currently well established theory in psychopharmacology that lithium increases mitochondrial calcium.


    [​IMG]


    Fig. 1. Role of mitochondria in intracellular calcium signaling.

    Intracellular calcium level is maintained low, but two organelles, endoplasmic reticulum and mitochondria, have high levels of calcium. Mendelian diseases that accompany bipolar disorder are the diseases of these two organelles.

    GPCR, G protein coupled receptor; PIP2, Phosphatidylinositol 4,5-bisphosphate; I-1-P, inositol 1-phosphate; IP3. Inositol triphosphate; IP3-R, inositol triphosphate receptor; Bcl-2, B-cell lymphoma 2.
     
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  8. S-VV

    S-VV Senior Member

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    That's very interesting. Your high HTMA Ca, (suggesting low celular Ca), the low ionic Ca and the positive response to lithium are very indicative of low mitochondrial Calcium.

    Now if we could find out why you initially felt better on T3 and then worse, it would be a great step forward. Did T3 move Ca into the cytosol/ mitochondria at the expense of Ca reserves elsewhere?
     
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  9. Iritu1021

    Iritu1021 Breaking Through The Fog

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    I think that's because taking external T3 is not physiologic (unless it's tiny doses under 1 mcg in slow release form which is a weak approximation of what would be released by thyroid gland itself).
    Each peak dose of T3 creates a hyperthyroid spike which further depletes calcium reserves and forces the cells to shut down metabolic rate even further, to decrease cellular thyroid transport, deiodinaton, so by the time the dose wears off, you are actually left more hypothyroid and with less calcium in your cells than you had before - thus creating a vicious cycle of needing to increase the dose to achieve the same effect.

    @debored13
     
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  10. debored13

    debored13 Senior Member

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    Vermont, school in Western MA
    You know i'm into the ray peat thing, but it's interesting as he is not into super high doses and says that the doses he recommends are physiological! but he's talking more in the 3-5 mcg range

    I will eventually look more into this

    One thing peat says tho is that T3 with a meal should be slow release essentially
     
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  11. S-VV

    S-VV Senior Member

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    Then the correct approach would be to increase miyo
    One thing I don't get. The NCLX is an efflux exchanger of Ca out of the Mitochondria. Lithium can be efficiently exchanged for Ca. This raises cytosolic Ca, but wouldn't it lower mitochondrial Ca?
     
  12. Iritu1021

    Iritu1021 Breaking Through The Fog

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    I suspect that the concentration of lithium is negligible compared to the concentration of sodium, so the effect you get from the increased cytosolic gradient will override the minor losses from this one. That's just me speculating.
     
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  13. S-VV

    S-VV Senior Member

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    Makes sense, thanks! So, if we know that increasing [Ca]m can have therapeutic effects, what other substances may be employed?

    We have two ways of increasing [Ca]m:

    - Increase calcium in the cytosol, and let the gradient do the rest
    - Increase the activity of the MCU
     
  14. Iritu1021

    Iritu1021 Breaking Through The Fog

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    Ray Peat is an interesting guy but to my knowledge he did not have ME/CFS or POTS so his experience would not be relevant to my own. This is why I have nothing to debate with him - he and I do not have the same condition. I suspect that he was probably treating himself for depression with high doses of thyroid. People with depression generally tend to respond well to high doses of T3 while people while people with severe CFS do not. There is a blog from a guy in Australia who went from having moderate CFS to not being able to leave his bed for the last ten years after taking T3 for a couple weeks.

    It's also my impression that Ray Peat no longer believes most of what he said a long time ago, which is why he removed all his books and has tried to distance himself from the disciples who developed protocols based on his ideas since he's against any "protocols" and mainly tried to teach people to make intuitive connections about their bodies, his "perceive. think. act" mantra.
     
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  15. Iritu1021

    Iritu1021 Breaking Through The Fog

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    It looks like MCU is so new that all the treatments are still in the early experimental stage so cytosolic calcium is probably the best bet for us at this time.
     
  16. Iritu1021

    Iritu1021 Breaking Through The Fog

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    Dandelion Root Extract Induces Intracellular Ca2+Increases in HEK293 Cells
    http://www.mdpi.com/1422-0067/19/4/1112

    Perhaps dandelion tea with milk as an alternative to coffee?
     
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  17. Gingergrrl

    Gingergrrl Senior Member

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    Would this test normally not be done outside of the ER or hospital (or would that be unusual)? My main doctor would order it if I asked him but I'd need to explain why I want it and how it would help or change my treatment. Once someone knows their level of ionized calcium (or active form?), what does that tell you from a treatment perspective?

    Fasting is no problem for me but I would not be able to stop Armour Thyroid or Vitamin D for a week so I guess I wouldn't be able to do this test anyway.

    They are considered "paraneoplastic autoantibodies" and the Mayo Panels can test both the N-type and the P/Q type which often correlate with LEMS or Small Cell Lung Cancer (SCLC) but other times they are random and do not correlate with any known illness.

    The Neuros that I saw told me explicitly that they act as a calcium channel blockers and I accepted this at face value and assume it to be accurate (although I cannot tell you why or how they work). I am negative for the P/Q type and positive for the N-type. There is also an L-type but I do not believe there is a test for this one.

    I have Hashimoto's (both Hashi's autoantibodies and hypothyroid when not on Armour) but I don't know much re: Graves. I was tested for the Graves autoantibody once, just to rule it out, and it was negative.

    I read the prior posts but did not understand what MCU was. Is it an experimental med that acts as a calcium channel opener (like what Drob31 mentioned above) or something different?
     
  18. pattismith

    pattismith Senior Member

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    T3 and caffeine only open calcium channels from the sarcoplasmic reticulum (a place inside the cell where calcium is stored), but I don't know which chanels are activated (maybe the RyR?)
    However, these channels are differents from the calcium voltage gated channels , and I don't know if caffeine have any effect on these ones.

    [​IMG]
     
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  19. Gingergrrl

    Gingergrrl Senior Member

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    Patti, Thanks for explaining that (re: T3 and caffeine opening only certain CA+ Channels that are not the voltage gated ones). I assume most of this thread doesn't pertain to my situation after all but I was not certain (and it was interesting to read regardless)!
     
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  20. Iritu1021

    Iritu1021 Breaking Through The Fog

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    You can try doing it without stopping, just don't take Armour until after the test. It might not be accurate but still worth a try.

    I only used Grave's as an example of an activating antibody. I have Hashimoto's too.

    It's a recently discovered protein transporter that uptakes calcium into mitochondria. The channels you are talking about are in the cellular membranes but I suppose that if you have something that blocks Ca entrance into cells it will lead to low intracellular calcium and therefore low mitochondrial calcium, which in turn leads to mitochondrial dysfunction.
     
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