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

hixxy

Senior Member
Messages
1,229
Location
Australia
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
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
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.
 

Kati

Patient in training
Messages
5,497
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.

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!
 

Gingergrrl

Senior Member
Messages
16,171
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.

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.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
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.
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.
 

allyann

Senior Member
Messages
418
Location
Melbourne Australia
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
 

lansbergen

Senior Member
Messages
2,512
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.

The immune modulator I use decreases cAMP and increases cGMP.
 

FMMM1

Senior Member
Messages
513
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?
 

Marky90

Science breeds knowledge, opinion breeds ignorance
Messages
1,253
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.
 

Marky90

Science breeds knowledge, opinion breeds ignorance
Messages
1,253
Interestingly my blood calcium levels are somewhat high for no obvious reason, wonder if it could be related to this
 

FMMM1

Senior Member
Messages
513
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!
 

Gingergrrl

Senior Member
Messages
16,171
@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!