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

[FMMM1]

Gingergrrl - you can imagine my surprise when I read an email which stated that I had "read the whole paper --- and had a good grasp of it"! Then I noticed that your post was addressed to "Marky 90".

First of all I think Alex is correct i.e. this (autoimmunity) wasn't the research question.

I seems to recall something online from someone close to the Australian team (Griffith) that basically everyone has been barking up the wrong tree (infection - virus etc). Presumably they are saying that some people with ME/CFS have a faulty sensor (TRPM3) or other (-- calcium ion channelopathy?).

In terms of the cause (specifically autoimmunity affecting e.g. TRPM3) I've an interest. Angela Vincent (Oxford University) and S Irani published a paper re autoimmune forms of VGPC epilepsy. I.e. there were less common forms of the disease which were autoimmune. These autoimmune forms didn't respond to the normal medicines but responded to immunosuppressents. So possibly some forms of ME/CFS are caused by a faulty sensor (TRPM3) or other and a portion of these are autoimmune. Angela Vincent was interested in doing a comprehensive search for autoantibodies in ME/CFS; I'm not clear where that got to, but at least Vicky Whittemore (NIH) has promised to increase funding, so it may happen. Response to rituximab suggests autoimmunity but not everyone responds so perhaps only the responders have an autoimmune form.

PS if anyone bumps into the folks who decide what gets funded (i.e. politicians, policy makers etc) then perhaps they could have a word re funding a comprehensive search for autoantibodies.

 

[Bob]

PS if anyone bumps into the folks who decide what gets funded (i.e. politicians, policy makers etc) then perhaps they could have a word re funding a comprehensive search for autoantibodies.

That would be a great suggestion to submit to the NIH"s request for information.

 

[FMMM1]

Please feel free to submit (to NIH's request for information) something along those lines. I.e. positive response to rituximab may indicate immune forms. Comprehensive search for autoantibodies (including those focused on TRPM3) may provide means to diagnose and treat autoimmune forms. I've done something (very roughly) along those lines.

By the way the phrase (in my previous post) that everyone's been barking up the wrong tree of course fails to acknowledge the similarities in the hypothesis proposed by the Griffith's team and the Light (2008?) study and the 1999 study by Chaudhuri and Behan et al.

 

[Snow Leopard]

The previous SNP findings were not interesting at all, failing to have significant results when correcting for multiple comparisons, but this current finding is mildly interesting. I'm not so sure where it all fits together though.

"TRPM3 is a nociceptor channel involved in the detection of noxious heat."
http://www.ncbi.nlm.nih.gov/pubmed/24795573

"Transient receptor potential M3 channels are ionotropic steroid receptors in pancreatic β cells"
http://www.nature.com/ncb/journal/v10/n12/full/ncb1801.html

"A TRP channel-steroid marriage"
http://www.nature.com/ncb/journal/v10/n12/full/ncb1208-1383.html
¯\_(ツ)_/¯

 

[FMMM1]

Interesting snow leopard. If you check out the "followmeindenmark" website it contains the following: "I have seen individual analysis data from the ME patients who exhibit signs of impaired cholesterol metabolism and decreased levels of pregnenolone".

I recall a scientist saying they were interested in measuring hormone (steroid) levels in ME/CFS - possibly something to submit to the NIH"s request for information.

I've no idea how a faulty TRPM3 receptor results in low pregnenolone.

Anyone know of a link between ME/CFS and altered hormone levels?

 

[A.B.]

Anyone know of a link between ME/CFS and altered hormone levels?

It's commonly accepted that patients with ME/CFS tend to have hormones on the low side (but some can also be increased). Decreased pregnenolone fits the general picture, as it is a precursor to testosterone and cortisol as well as other hormones. This probably starts in the brain, with the hypothalamus being set to this low endocrine output state for reasons unknown.

I think the suggestion is that the impaired cholesterol metabolism is an alternative (and more concrete) explanation for why hormones tend to be on the low side.

 

[Gingergrrl]

Gingergrrl - you can imagine my surprise when I read an email which stated that I had "read the whole paper --- and had a good grasp of it"! Then I noticed that your post was addressed to "Marky 90".

@FMMM1 Just wanted to keep you on your toes LOL.

Presumably they are saying that some people with ME/CFS have a faulty sensor (TRPM3) or other (-- calcium ion channelopathy?).

Am certain this is the group I am in, whether my ultimate diagnosis is ME/CFS or not, I wish there was more research on ion channelopathies in general. I suspect it plays a major role for many of us.

Angela Vincent was interested in doing a comprehensive search for autoantibodies in ME/CFS; I'm not clear where that got to, but at least Vicky Whittemore (NIH) has promised to increase funding, so it may happen.

My doctor said that Angela Vincent discovers new auto-antibodies every week LOL. I am very heartened to know that Vicky Whittemore has promised to increase funding for this type of research. Great news!

Response to rituximab suggests autoimmunity but not everyone responds so perhaps only the responders have an autoimmune form.

Were patients tested for auto-antibodies in any of the research studies prior to receiving RTX so it can be correlated with who is a responder?

PS if anyone bumps into the folks who decide what gets funded (i.e. politicians, policy makers etc) then perhaps they could have a word re funding a comprehensive search for autoantibodies.

Absolutely and I wish I had some kind of connections to do this but sadly do not!

 

[Snow Leopard]

Interesting snow leopard. If you check out the "followmeindenmark" website it contains the following: "I have seen individual analysis data from the ME patients who exhibit signs of impaired cholesterol metabolism and decreased levels of pregnenolone".

I recall a scientist saying they were interested in measuring hormone (steroid) levels in ME/CFS - possibly something to submit to the NIH"s request for information.

I've no idea how a faulty TRPM3 receptor results in low pregnenolone.

Anyone know of a link between ME/CFS and altered hormone levels?

Pregnenolone sulfate activity is different to Pregnenolone, but...

The following study (only one I have seen) found no difference in Pregnenolone levels in (Fukuda) patients compared to controls.
http://www.sciencedirect.com/science/article/pii/S030645300300026X

 

[FMMM1]

Re research on hormone levels in ME/CFS, thanks again snow leopard.

I hope you don't mind me asking this but I once went to a talk on Huntington's disease which is caused by an inherited faulty gene. My (limited) understanding is that the fault could be on a number of places on the gene but still result in the disease. If you looked at a single SNP in Huntington's disease and did the sums would the probability be less than 0.05 (i.e. significant) or would it be greater than 0.05 i.e. not statistically significant. Obviously some SNPs give rise to a genetic condition and some do not (silent mutations) so the maths seems complicated i.e. until you work out which SNPs are silent. I wondering if there's something similar going on re stats for TRPM3 etc.

Thanks again.

 

[wastwater]

Maybe this guy could shed some light on cyclic AMP and calcium signalling http://www.phar.cam.ac.uk/research/Cooper

 

[FMMM1]

I assume that "this guy" is Prof. Dermot Cooper (retired). I've only looked at this for a few moments but in terms of "cyclic AMP and calcium signalling" the following may be relevant (or not). In terms of "cyclic AMP" the following is from Wikipedia:

"Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transduction in many different organisms, conveying the cAMP-dependent pathway."


and the following from the Follow ME in Denmark website:


ME / CFS patients have too little ATP (energy)

Chantalle Moolman from North West University South Africa has released this thesis: Quantification of selected energy and redox markers in blood samples of chronic fatigue syndrome patient As stated in the introduction, there are now many articles that points mitochondrial dysfunction, oxidative stress and energy shortages in ME / CFS patients. This problem is linked to the cells' basic functions, and it is difficult to measure.


The problem with the ATP study was that they couldn’t stabilise ATP and therefore couldn’t diagnose low ATP in individual patients (the comparison showing low ATP levels was for groups).


It is interesting to see a possible link between calcium signalling (Griffith University Research) and cAMP (and ATP) – if I understand this correctly!


Ron Davis (among others) has been looking for biomarkers and there have been rumours of a significant finding.


Hopeful we’ll see some significant progress re biomarkers

 

[JaimeS]

"I have seen individual analysis data from the ME patients who exhibit signs of impaired cholesterol metabolism

*raises hand*

 

[FMMM1]

*raises hand*

Hi,
I'm not sure if this is relevant but Jonas Bergquist has been funded by OMF to do a steroid hormone study*.

Also, when I read this article regarding PDK and PDH in sepsis [https://www.healthrising.org/blog/2...e-cfs-research-center-fulfills-crucial-need/] I remembered your excellent article on Fluge and Mella’s paper showing PDK and SIRT4-mediated inhibition of PDH in ME/CFS [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/].
Interesting how sepsis and ME/CFS may have similar effects.


*Extract from OMF website [https://www.omf.ngo/experts-blog/]:
Cerebrospinal Fluid Research Update from Jonas Bergquist
What are the roles of hormones, proteins, and antibodies in ME/CFS? To answer these questions, OMF is currently funding the research of Jonas Bergquist, MD, PhD, a Professor at Uppsala University and a member of our Scientific Advisory Board. Dr. Bergquist is measuring proteins in cerebrospinal fluid and blood plasma from a small cohort of Swedish