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Novel identification and characterisation of Transient receptor potential melastatin 3 ion channels

Discussion in 'Latest ME/CFS Research' started by hixxy, May 31, 2016.

  1. hixxy

    hixxy Senior Member

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    https://biolres.biomedcentral.com/articles/10.1186/s40659-016-0087-2

    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
    • T. Nguyen,
    • D. Staines,
    • B. Nilius,
    • P. Smith and
    • S. Marshall-Gradisnik
    Biological Research201649:27
    DOI: 10.1186/s40659-016-0087-2

    © The Author(s) 2016

    Received: 26 January 2016

    Accepted: 9 May 2016

    Published: 31 May 2016

    Abstract
    Background
    Transient receptor potential melastatin 3 (TRPM3) cation channels are ubiquitously expressed by multiple cells and have an important regulatory role in calcium-dependent cell signalling to help maintain cellular homeostasis. TRPM3 protein expression has yet to be determined on Natural Killer (NK) cells and B lymphocytes. Multiple single nucleotide polymorphisms have been reported in TRPM3 genes from isolated peripheral blood mononuclear cells, NK and B cells in Chronic fatigue syndrome/Myalgic encephalomyelitis (CFS/ME) patients and have been proposed to correlate with illness presentation. The object of the study was to assess TRPM3 surface expression on NK and B lymphocytes from healthy controls, followed by a comparative investigation examining TRPM3 surface expression, and cytoplasmic and mitochondrial calcium influx in CD19+ B cells, CD56bright and CD56dim cell populations from CFS/ME patients.

    Results
    TRPM3 cell surface expression was identified for NK and B lymphocytes in healthy controls (CD56bright TRPM3 35.72 % ± 7.37; CD56dim 5.74 % ± 2.00; B lymphocytes 2.05 % ± 0.19, respectively). There was a significant reduction of TRPM3 surface expression on CD19+ B cells (1.56 ± 0.191) and CD56bright NK cells (17.37 % ± 5.34) in CFS/ME compared with healthy controls. Anti-CD21 and anti-IgM conjugated biotin was cross-linked with streptavidin,and subsequently treatment with thapsigargin. This showed a significant reduction in cytoplasmic calcium ion concentration in CD19+ B lymphocytes. CD56bright NK cells also had a significant decrease in cytoplasmic calcium in the presence of 2-APB and thapsigargin in CFS/ME patients.

    Conclusions
    The results from this preliminary investigation identify, for the first time, 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. This warrants further examination of these pathways to elucidate whether TRPM3 and impaired calcium mobilisation has a role in CFS/ME.

    Keywords
    Chronic fatigue syndrome Transient receptor potential Calcium signalling Myalgic encephalomyelitis
     
  2. alex3619

    alex3619 Senior Member

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    Impaired calcium mobilization might be tricky. I do not know the details of the mechanisms, but I do know that low ionized calcium might result in huge calcium burst release inside the cell when it is stimulated. This paper is early in a process of figuring stuff out, and its too soon to say if its a core mechanism or secondary.
     
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  3. Kati

    Kati Patient in training

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    This paper was submitted in January. It means that this team is already much further into discoveries and plans of attack than what is published. Moreover, Invest in ME is happening now, and we might just learn more this week about what they're up to.

    Nice going, Griffith University!
     
    Groggy Doggy, Mel9, Theodore and 7 others like this.
  4. Gingergrrl

    Gingergrrl Senior Member

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    Does this relate to calcium channel autoantibodies or is the paper discussing something totally different? I wish I could understand these papers at a higher level.
     
  5. alex3619

    alex3619 Senior Member

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    From the abstract, I have not yet read the paper, we don't know. It also does not look like this was a research question they were looking at.
     
  6. Gingergrrl

    Gingergrrl Senior Member

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    Thank you and much appreciated.
     
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  7. allyann

    allyann Senior Member

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    This was the message that they released on their Facebook page -

    Today, NCNED published an important paper reporting a significant reduction in TRPM3 cell surface expression in NK and B lymphocytes, as well as decreased intracellular calcium within these cell types. As this receptor is located on almost all human cells and tissues, this raises the question as to whether similar changes of TRPM3 expression or function of these receptors promotes more widespread disruption of intracellular signalling homeostasis in CFS/ME patients.
    This paper is an important finding. We thank every one of our donors and participants for supporting us.
    Best wishes
    Sonya, Don and the NCNED Team
    https://biolres.biomedcentral.com/articles/10.1186/s40659-016-0087-2
     
    Theodore, Daisymay, MEMum and 2 others like this.
  8. Bob

    Bob

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    Note that it's open access.

    (There's a Phoenix Rising prize to the first person to read it and fully understand it!) :) (Note: that's a joke - no prizes are available.)
     
    picante, GreyOwl, moosie and 11 others like this.
  9. Gingergrrl

    Gingergrrl Senior Member

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    I won't be getting the prize (real or imaginary) but I like the idea!
     
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  10. Valentijn

    Valentijn WE ARE KINA

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    I'm pretty sure there's a forum prize called "The Bob", which has many uses :star::trophy::star:
     
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  11. Bob

    Bob

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    Ah, so you remember "The Bob"! :) Yes, it has many uses. But it's a bit slow and befuddled!
     
    Last edited: Jun 19, 2016
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  12. wastwater

    wastwater Senior Member

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    Last edited: Jun 1, 2016
    Theodore and Kati like this.
  13. alex3619

    alex3619 Senior Member

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    Calcium and cAMP are primary intracellular regulators, kind of hormones. They are criticial to switching many things on, and can be involved in keeping things switched off.

    What we do not know is why there is this problem. If they can find out then we will have advanced the science a fair bit.
     
  14. lansbergen

    lansbergen Senior Member

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    The immune modulator I use decreases cAMP and increases cGMP.
     
  15. alex3619

    alex3619 Senior Member

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    Let me also point out that ATP availability can also modulate processes, and we have too little.
     
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  16. FMMM1

    FMMM1

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    I haven't read the paper. I attended the invest in ME conference yesterday and if I understood correctly there are further papers due to be published (6?) setting out further research findings re mechanism.
    The presentation at the conference included data re SNPs on the TRPM3 gene and from that I'm guessing that the hypothesis is that there is a genetic basis for these patients. So, I'm not sure how autoimmunity would fit in with a genetic hypothesis. I'm not a mathematician but the figures re genetic markers looked impressive.
    Well done to all involved in this research.
    I'd a very early start yesterday, so I'm sure I (slept through) missed a fair bit of the conference.

    Re impaired/altered (intracellular) calcium signalling - how would you measure that?
     
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  17. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    After reading the paper, I am quite excited

    "These calcium-mediated TRP functions contribute to a number of cellular processes and cellular functions. These processes include regulating enzymatic function and transcription factors, lymphocyte proliferation and differentiation of naïve cells into effector and memory cells as well as the production of cytokines and chemokines (see review [8]). TRPM3 alone or in conjunction with TRPC members, members of the TRPV1 family, together with muscarinic M3 receptors [40] and calcium release activated calcium (CRAC) channels [41] may need to be considered for calcium intracellular-mediated roles."

    I had not even heard of TRPs, but it seems from above that it could potentially be closely linked to the causative agent(s) of this disease.
     
    RL_sparky likes this.
  18. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    Interestingly my blood calcium levels are somewhat high for no obvious reason, wonder if it could be related to this
     
  19. FMMM1

    FMMM1

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    Hi you may wish to note that NIH has published a "Request for Information: Soliciting Input for New Research Strategies for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)" search the web for the words in commas - Responses will be accepted through June 24, 2016.

    It would be interesting to see how these genetic markers (on TRPM3 etc) compare to MIRNA markers (I'm assuming that's one of the things the Australian researchers have been looking at) and protein biomarkers - check out James Baraniuks' 2004(?) paper and Jonas Bergquist's presentation at the 2015 conference re proteins.

    The researchers, from the University College London (UCL), at the Invest in ME conference (2016) who presented on autoimmunity seemed pretty clear that there was evidence of autoimmunity (based on improvement after Rituximab was given). Autoimmunity correlated with genetic markers (on TRPM3 etc)?

    If I understand correctly James Baraniuk is due to publish re MIRNA---

    At least those folks are doing science --- £5 million on PACE Trial!
     
    Kati likes this.
  20. Gingergrrl

    Gingergrrl Senior Member

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    @Marky90 Since you have read the whole paper (I think?) and have a good grasp of it, are they referring to the n-type calcium channel auto-antibodies and if so, what do they suggest or recommend? Would love to hear more how you interpreted it!
     

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