Nguyen et al/NCNED: Calcium mobilisation in NK cells from CFS/ME patients is associated with...

[RogerBlack]

My understanding is that calcium supplementation would do nothing. I may be wrong.

 

[duncan]

Does this mean ME/CFS could be qualified as a calcium channelopathy?

 

[alex3619]

Does this mean ME/CFS could be qualified as a calcium channelopathy?

Maybe. I have yet to read the full paper. What I think this might imply is a problem in intracellular ionized calcium regulation, which is ironic since I have been thinking about such things since about 2000 but have never been able to demonstrate it. Ionized calcium, and their opposition from cyclic AMP, represent important regulators of intracellular chemistry. A deficiency or imbalance will derange much of the biochemistry of the cell. The effects could be very broad at the intracellular chemistry level.

One type of issue resulting in this would be a channelopathy, but I am unsure this is the only potential cause.

 

[alex3619]

Transient receptor potential (TRP) ion channels modulate ion entry in the cell plasma membrane, and are expressed differentially on tissues throughout the body.

It would be interesting to take a look at what tissues express what types of TRP.

So far I am considering this issue as an association, not causation, but if they could actually prove this as a causal mechanism ....

 

[alex3619]

Aim of the study:

Therefore, the objective of this study was to determine the effects of PregS on TRPM3, including CD69 and CD107a receptor expression in NK cells. Additionally, we investigated intracellular Ca2+mobilization and cytotoxic activity of NK cells after PregS treatment in HC and CFS/ME patients.

 

[Daisymay]

Does anyone have any idea why there would be this calcium metabolism problem in NK cells but not in other cells, or is this problem present in all our cells?

 

[alex3619]

Increasing Ca2+ concentrations to activate the ERK signalling pathway may help to improve NK cell cytotoxicity in CFS/ME

A potential drug target.

Taking into account this unproven hypothesis:

Other TRP receptors, such as TRPM1, may possibly have a similar role in CFS/ME pathomechanism due to its sequence homology with TRPM3; however, further investigation is warranted

... then we have a potential broad mechanism affecting many tissues under many circumstances. I think this is also a potential explanation for your question @Daisymay. They hypothesize its in many cell types, but this remains unproven.

 

[alex3619]

TRPM3 ion channels are expressed in various tissues, predominantly in sensory neurones, kidney, brain, pituitary gland and pancreas. While expressed ubiquitously in mammalian cells, the roles and functions of TRPM3 have yet to be determined in immune cells

If this is a causal pathophysiology, and applies to all TRPM3 types (which it might not) then we can see a big issue in the nervous system, as well as hormone regulation.

 

[alex3619]

My brain is not currently up to remembering enough stuff at the same time to really get to grips with this, but it appears that the problem might not be a channelopathy with damaged calcium channels (though I could be wrong) but rather in regulation of calcium channels and hence calcium availability.

 

[alex3619]

Let me caution people that improving NK cell function through increased intracellular ionized calcium might not do much to improve ME or CFS, but rather it may be a further clue as to what is happening. However if similar ion channel problems exist in other cell types, yet to be confirmed, then strategies along these lines might be helpful. This would come at some risk though, as inducing a further imbalance in Ca++/cAMP signalling could have many unintended consequences. We need the science to advance.

 

[Daisymay]

A potential drug target.

Taking into account this unproven hypothesis:



... then we have a potential broad mechanism affecting many tissues under many circumstances. I think this is also a potential explanation for your question @Daisymay. They hypothesize its in many cell types, but this remains unproven.

Thanks @alex3619. Do you know if in general, metabolic problems tend to occur in all cell types throughout the body or is it normal for them to be organ or cell type specific?

 

[alex3619]

Thanks @alex3619. Do you know if in general, metabolic problems tend to occur in all cell types throughout the body or is it normal for them to be organ or cell type specific?

Both. It depends on the problem. We have a lot to learn about this one. What we do know is that for many receptor subtypes there are a specific range of cells affected. However we do not know if this problem is specific to a subtype, or to TRPM receptors in general, or something in between.

 

[JES]

Maybe. I have yet to read the full paper. What I think this might imply is a problem in intracellular ionized calcium regulation, which is ironic since I have been thinking about such things since about 2000 but have never been able to demonstrate it. Ionized calcium, and their opposition from cyclic AMP, represent important regulators of intracellular chemistry. A deficiency or imbalance will derange much of the biochemistry of the cell. The effects could be very broad at the intracellular chemistry level.

One type of issue resulting in this would be a channelopathy, but I am unsure this is the only potential cause.

My old blood laboratory reports show serum calcium above reference range and ionized calcium right in the bottom of the range. Maybe has nothing to do with this, but it's another peculiar finding.

 

[nandixon]

For the other scientists out there, the present study appears very consistent with the impaired sphingosine-1-phosphate (S1P) signaling hypothesis (see my signature), and I believe the findings are what would be expected if either S1P levels are too low or if there are autoantibodies against a S1P receptor.

S1P signaling is a critical regulator of intracellular calcium concentration/flux and is mediated by S1P both through its receptors (e.g., S1PR1 aka S1P1) on the cell surface and also within the cell itself independently of any receptor. (There are several dozen potential references. See this PubMed search string.)

So, IMO, the TRPM3 receptors are not going to be the primary problem here, but rather impaired S1P signaling, and the modest reductions in function that any single nucleotide polymorphisms (SNPs) in the TRPM3 gene may be making are likely just exacerbating the problem.

 

[eljefe19]

@nandixon You're the man! It's probably both options or some combination of both when you consider Rituximab high responders vs. low responders vs. non responders, right? As in, those with predominantly autoantibodies causing the issue will respond?

 

[nandixon]

@eljefe19, It's not clear what rituximab's mode of action is in ME/CFS. It may or may not be having an anti-autoimmune effect. If there is impaired S1P signaling, though, it seems more likely to me that the impairment would be due to either low S1P or autoantibodies against the receptors but not both.

 

[nandixon]

Interestingly, this 2005 study found that sphingosine but not S1P (which is made from sphingosine) activated TRPM3.

(Note that the activation of TRPM3 is a closely related yet separate issue from the possibility of there being impaired S1P signaling causing poor calcium flux.)

 

[hixxy]

Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channels

T. Nguyen, S. Johnston, L. Clarke, P. Smith, D. Staines, and S. Marshall‐Gradisnik

SUMMARY

Transient receptor potential melastatin subfamily 3 (TRPM3) ion channels play a role in calcium (Ca2+) cell signalling. Reduced TRPM3 protein expression has been identified in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) patients. However, the significance of TRPM3 and association with intracellular Ca2+ mobilization has yet to be determined. Fifteen CFS/ME patients (mean age 48·82 ± 9·83 years) and 25 healthy controls (mean age 39·2 ± 12·12 years) were examined. Isolated natural killer (NK) cells were labelled with fluorescent antibodies to determine TRPM3, CD107a and CD69 receptors on CD56dimCD16+NK cells and CD56brightCD16dim/– NK cells. Ca2+ flux and NK cytotoxicity activity was measured under various stimulants, including pregnenolone sulphate (PregS), thapsigargin (TG), 2‐aminoethoxydiphenyl borate (2APB) and ionomycin. Unstimulated CD56brightCD16dim/– NK cells showed significantly reduced TRPM3 receptors in CFS/ME compared with healthy controls (HC). Ca2+ flux showed no significant difference between groups. Moreover, PregS‐stimulated CD56brightCD16dim/–NK cells showed a significant increase in Ca2+ flux in CFS/ME patients compared with HC. By comparison, unstimulated CD56dimCD16+ NK cells showed no significant difference in both Ca2+ flux and TRPM3 expression. PregS‐stimulated CD56dimCD16+ NK cells increased TRPM3 expression significantly in CFS/ME, but this was not associated with a significant increase in Ca2+ flux. Furthermore, TG‐stimulated CD56dimCD16+ NK cells increased K562 cell lysis prior to PregS stimulation in CFS/ME patients compared with HC. Differential expression of TRPM3 and Ca2+ flux between NK cell subtypes may provide evidence for their role in the pathomechanism involving NK cell cytotoxicity activity in CFS/ME.

Keywords: cell surface molecules, inhibitory/activating receptors, natural killer cells

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217865/
http://onlinelibrary.wiley.com/doi/10.1111/cei.12882/full

 

[trishrhymes]

Can anyone translate this into words I can understand?

 

[M Paine]

This paper has been covered here:

Calcium mobilisation in natural killer cells from Chronic fatigue syndrome/Myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channels