Ion Channel Problems Found in ME/CFS!

[Cort]

We've been talking a lot about ion channel problems in chronic pain but the NCNED group in Australia just found ion channel problems in ME/CFS as well. An neurological ion channelopathy was actually conjectured to be present in ME/CFS by Chaudhuri and Behan, I think it was, about 15 years ago. The authors suggested the problems they found could affect nerve functioning.

The ion channels measured mediate a variety of sensations like the sensations of pain, hotness, warmth or coldness, different kinds of tastes, pressure, and vision. Remarkably, nine of the polymorphisms more commonly found in ME/CFS take place in one ion channel - the TRPM ion channel. These channels regulate the flows of magnesium and calcium into the cells and have been implicated in inflammatory pain syndromes, rheumatoid
arthritis, the secretion of proinflammatory cytokines, metabolic problems, pain and possibly glutamergic signaling.

Exciting stuff. Ion channels are big in pain research now...Better techniques allow researchers to better understand them. It's definitely a growth field.

I attached the paper.

• http://www.la-press.com/examination...rphisms-snps-in-transient-recep-article-a4824

Background: The transient receptor potential (TRP) superfamily in humans comprises 27 cation channels with permeability to monovalent and divalent cations. These channels are widely expressed within humans on cells and tissues and have significant sensory and regulatory roles on most physiological functions. Chronic fatigue syndrome (CFS) is an unexplained disorder with multiple physiological impairments.

Objectives: The purpose of this study was to determine the role of TRPs in CFS.

Methods: The study comprised 115 CFS patients (age = 48.68 ± 1.06 years) and 90 nonfatigued controls (age = 46.48 ± 1.22 years). CFS patients were defined according to the 1994 Center for Disease Prevention and Control criteria for CFS. A total of 240 single nucleotide polymorphisms (SNPs) for 21 mammalian TRP ion channel genes (TRPA1, TRPC1, TRPC2, TRPC3, TRPC4, TRPC6, TRPC7, TRPM1, TRPM2, TRPM3, TRPM4, TRPM5, TRPM6, TRPM7, TRPM8, TRPV1, TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6) were examined via the Agena Biosciences iPLEX Gold assay. Statistical analysis was performed using the PLINK analysis software.

Results: Thirteen SNPs were significantly associated with CFS patients compared with the controls. Nine of these SNPs were associated with TRPM3 (rs12682832; P ≤ 0.003, rs11142508; P < 0.004, rs1160742; P < 0.08, rs4454352; P ≤ 0.013, rs1328153; P ≤ 0.013, rs3763619; P ≤ 0.014, rs7865858; P ≤ 0.021, rs1504401; P ≤ 0041, rs10115622; P ≤ 0.050), while the remainder were associated with TRPA1 (rs2383844; P ≤ 0.040, rs4738202; P ≤ 0.018) and TRPC4 (rs6650469; P ≤ 0.016, rs655207; P ≤ 0.018).

Conclusion: The data from this pilot study suggest an association between TRP ion channels, predominantly TRPM3 and CFS. This and other TRPs identified may contribute to the etiology and pathomechanism of CFS.

 

[Issie]

Interesting. I just found out one of the meds I've been on for MCAS is a mild calcium channel blocker. I'm trying to come off it - very expensive. We will see what happens when that aid is not there. It had been one of my best POTS meds too.

Issie

 

[Issie]

Oh my doc won't let me supplement with magnesium (other than what is in my whole foods. As a vegan I get a lot of my minerals and vitamins that way ) it reinforces the biofilm that shields virus, bacteria and Protozoa. We want to break that down so the immune system can notice them and eradicate what it can/will.

Issie

 

[Cort]

Griffiths released this:

New research findings may shed light on the potential cause of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME).
Researchers from Griffith University’s National Centre for Neuroimmunology and Emerging Diseases (NCNED) – part of the new Menzies Health Institute Queensland – have uncovered significant factors contributing to the pathology of this illness.

The results reveal genetic changes in important receptors associated with immunological and cellular function and contribute to the development of this complex illness.

“These findings have been achieved through a team effort involving researchers, patients, funding bodies, clinicians and the support of Griffith University and the Queensland Government,” say chief investigators Professor Sonya Marshall-Gradisnik and Professor Donald Staines.
Co-researcher and consultant immunologist Professor Pete Smith said that important signalling mechanisms are disrupted as a result of these genetic changes involving the detection and response to threats.

“These are primitive genes that are involved in many cellular signals in the brain, gut, cardiovascular and immune systems, as well as in the mediation of pain.”

These research findings coincide with International Neuroimmune Awareness week commencing Monday 11 May.'

The Griffith Health Centre on the university’s Gold Coast campus is being lit up each evening from 10 -12 May to raise awareness of neurological conditions such as CFS/ME as well as other conditions such as Fibromyalgia and Gulf War Syndrome.

“The lighting up of the Griffith Health Centre signifies Griffith’s commitment to the CFS patient community and our team approach to this research,” says Pro-Vice Chancellor (Health) Professor Allan Cripps.

CFS/ME is a highly debilitating disorder characterised by profound fatigue, muscle and joint pain, cerebral symptoms of impaired memory and concentration, impaired cardiovascular function, gut disorder and sensory dysfunction such as noise intolerance and balance disturbance. Many cases can continue for months or years. It is believed to affect around 250,000 Australians.

The research findings are to be presented at an international conference in London later this month.

 

[Cort]

 

[Remy]

Oh my doc won't let me supplement with magnesium. It reinforces the biofilm that shields virus, bacteria and Protozoa. We want to break that down so the immune system can notice them and eradicate what it can/will.

Issie

I think that it's a little shortsighted and simplistic to shun magnesium supplementation because it can reinforce biofilm formation. Basically all minerals, especially calcium, can contribute to biofilm formation yet no one is suggesting we not eat our leafy greens. Biofilms flourish in general in any sort of nutrient rich environment but depleting ourselves to starve biofilm seems counterproductive at best.

We don't understand the complex subjects of biofilms and their formation well enough, in my opinion, to allow ourselves to become deficient in a mineral like magnesium that participates in so many important functions in the body. My LLMD is also of this mindset which also goes to show how many conflicting opinions there are on this and every other topic with relation to Lyme and co at this time.

Hopefully future research will help to make this all more clear.

 

[Issie]

Griffiths released this:

New research findings may shed light on the potential cause of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME).
Researchers from Griffith University’s National Centre for Neuroimmunology and Emerging Diseases (NCNED) – part of the new Menzies Health Institute Queensland – have uncovered significant factors contributing to the pathology of this illness.

The results reveal genetic changes in important receptors associated with immunological and cellular function and contribute to the development of this complex illness.

“These findings have been achieved through a team effort involving researchers, patients, funding bodies, clinicians and the support of Griffith University and the Queensland Government,” say chief investigators Professor Sonya Marshall-Gradisnik and Professor Donald Staines.
Co-researcher and consultant immunologist Professor Pete Smith said that important signalling mechanisms are disrupted as a result of these genetic changes involving the detection and response to threats.

“These are primitive genes that are involved in many cellular signals in the brain, gut, cardiovascular and immune systems, as well as in the mediation of pain.”

These research findings coincide with International Neuroimmune Awareness week commencing Monday 11 May.'

The Griffith Health Centre on the university’s Gold Coast campus is being lit up each evening from 10 -12 May to raise awareness of neurological conditions such as CFS/ME as well as other conditions such as Fibromyalgia and Gulf War Syndrome.

“The lighting up of the Griffith Health Centre signifies Griffith’s commitment to the CFS patient community and our team approach to this research,” says Pro-Vice Chancellor (Health) Professor Allan Cripps.

CFS/ME is a highly debilitating disorder characterised by profound fatigue, muscle and joint pain, cerebral symptoms of impaired memory and concentration, impaired cardiovascular function, gut disorder and sensory dysfunction such as noise intolerance and balance disturbance. Many cases can continue for months or years. It is believed to affect around 250,000 Australians.

The research findings are to be presented at an international conference in London later this month.

Wow. I've been saying I thought epigenetic changes is what triggered our immune systems into malfunctioning. Interesting info.

 

[Issie]

I think that it's a little shortsighted and simplistic to shun magnesium supplementation because it can reinforce biofilm formation. Basically all minerals, especially calcium, can contribute to biofilm formation yet no one is suggesting we not eat our leafy greens. Biofilms flourish in general in any sort of nutrient rich environment but depleting ourselves to starve biofilm seems counterproductive at best.

We don't understand the complex subjects of biofilms and their formation well enough, in my opinion, to allow ourselves to become deficient in a mineral like magnesium that participates in so many important functions in the body. My LLMD is also of this mindset which also goes to show how many conflicting opinions there are on this and every other topic with relation to Lyme and co at this time.

Hopefully future research will help to make this all more clear.

We get plenty of magnesium in our foods as vegans. It's the additional supplementation he doesn't want us to do. The goal is to have our bodies working and metabolizing so well we won't need hardly any supplements. Getting our minerals and vitamins in a whole food form that isn't so concentrated is a more balanced approach than individual supplementation. I used to be around and in the alternative supplement field. I can tell you what to take for what and what not to combine. Or what is counter indicated if you have this Or that illness. I've had years of experience with this. But my whole way of looking at supplementation has changed. I do still supplement. But not like I used to. I get it with my foods now.

Issie

 

[Remy]

We get plenty of magnesium in our foods as vegans

That's not the case for the vast majority of the people who might read your original post though and who could benefit from adequate supplementation, from increasing whole foods or from taking supplements.

I wasn't saying that you *should* take magnesium, only that it's simplistic to tell people to avoid a crucial nutrient because it may contribute to biofilm formation in some complex and largely unknown way.

 

[Issie]

That's not the case for the vast majority of the people who might read your original post though and who could benefit from adequate supplementation, from increasing whole foods or from taking supplements.

I wasn't saying that you *should* take magnesium, only that it's simplistic to tell people to avoid a crucial nutrient because it may contribute to biofilm formation in some complex and largely unknown way.

Ok I made my post a little more clear. So hopefully it will be understood better.

Issie

 

[Remy]

So these TRPs are pretty interesting even if it has taken me a whole year to get around to reading that article.

Here's @Cort's post on ProHealth on this study (I couldn't find it elsewhere on the forum but let me know if I missed it):

Australian Study Pinpoints Possible Gene Issues in Chronic Fatigue Syndrome

Reprinted with the kind permission of Cort Johnson and Health Rising.

By Cort Johnson

Much of the activity in nerve cells is regulated by very small channels that regulate the flows of ions such as calcium, sodium and magnesium in or out of the cells.

Given the central nervous system problems in ME/CFS and FM and the clear role ion channels in producing increased sensitivity to pain and stimuli, they would seem to be an obvious target for researchers. This study, though – from the NCNED Australian group – is the first to concentrate on them in ME/CFS.


The ion channels examined in this study mostly affect nerves. The ion channels examined in this study – the TRP channels – were recently called the “key transducers of nociception and pain”. (Neurons associated with the vagus nerve also contain many TRP ion channels.)

These channels trigger cells to respond to changes in their environment caused by pathogens, oxidative stress, chemicals, toxins and pH. These ion channels can be activated by numerous inflammatory by-products including toxins, cytokines and irritants.

Given the wide range of substances these ion channels react to having them bug out on you could lead to a lot of problems. Some researchers think the nervous system in ME/CFS and FM patients is over-reacting to stimuli. If it is it could start here.

Super sensitive ion channels could send pain and sensory signals coursing along the nerves to the brain at the slightest provocation. Translated into pain and other stimuli this barrage of sensory signals could hamper your ability to focus and think.

This study didn’t actually test ion channels; they looked for single nucleotide polymorphisms (SNP’s) in the genes governing how these ion channels function. SNP’s are very small changes in the genes that can alter how proteins and ultimately cells function. Some SNP’s produce no change (are benign), while others alter gene transcription in fundamental ways that produce physiological changes in how nerve and other cells function. For instance a SNP could cause an ion channel to open a bit more quickly in response to some stimulus thus telling the nerves to send pain or other signals more quickly to the brain.

Many SNP’s have been associated with diseases.

The Study
Immunology and Immunogenetics Insights 2015:7 1 Examination of Single Nucleotide Polymorphisms (SNPs) in Transient Receptor Potential (TRP) Ion Channels in Chronic Fatigue Syndrome Patients Sonya M. Marshall-Gradisnik1,2, Peter Smith2, Ekua W. Brenu1,2, Bernd Nilius3, Sandra B. Ramos1,2 and Donald R. Staines. 1. School of Medical Science, 2. The National Centre for Neuroimmunology

The Australian group examined 240 SNP’s in 21 genes governing TRP ion channel functioning (over ten per gene on average) in 115 people with chronic fatigue syndrome and 90 healthy controls.

Results
“These are primitive genes that are involved in many cellular signals in the brain, gut, cardiovascular and immune systems, as well as in the mediation of pain.”
In studies like this you hope to have some SNP’s show up but what you really hope to see are SNP’s concentrated in a couple of genes. Finding SNP’s concentrated in a couple of genes would suggest those genes are bad shape; bad enough shape to possibly contribute to disease.

That’s exactly what this study found. It found 13 small gene alterations nine of which were found in one of the 21 genes tested (TRPM3) and four of which were found in two other genes TRPC4/ TRPAI). With most gene alterations occurring in just three genes – the study hit a nice bulls-eye.

The results were close to being even more pinpoint. A fourteenth polymorphism that just barely missed significance (p<.051) was also associated with TRPM3 and two more polymorphisms for TRPA1 and TRPC4 (p<.065 / p< .068) were on the edge as well.

This is the second rather shockingly specific finding in the last year. The Stanford MRI study that found that almost all of the ME/CFS patients had alterations in a very, very small part of the brain (which none of the controls did) was the other. We rarely see such pinpoint results in ME/CFS.

The Genes

Two of the suspect ion channels are “thermosensory channels” (thermoTRP’s) that are activated by changes in temperature – putting a spotlight possibly on inflammation and thermoregulation. Studies indicate that the appearance of these channels in the sensory neurons is closely associated with the appearance of pain. Because they integrate several signaling pathways drug development to block them from functioning is being actively pursued.

TRPC4

The TRPC genes play important roles in memory, attention, sensory acuity, emotion, pain, and motor control in the amygdala, entorhinal cortex, hippocampus, and prefrontal cortex. The specific TRPC gene highlighted in this study – TRPC4 – can affect intestinal functioning and smooth muscle contraction.

TRPAI/TRPVI

TRPA1 regulates the activity of sensory neurons. Nerve fibers containing TRPA1 densely innervate the skin, airways and gastrointestinal tract. Pro-inflammatory and pain producing agents such as bradykinin, histamine, prostaglandins, and trypsin can all activate TRPA1. Once activated TRPA1 prompts the nerves to produce more pain and more inflammation. A super sensitized gene like TRPAI could go far to explain the pain problems in ME/CFS. The TRPA1 ion channel is a key player in the production of headaches and migraines.

TRPAI also interacts with the rather notorious TRPVI gene that has been implicated in migraine and other pain conditions. The two are so closely connected that it’s possible that a balky TRPAI ion channel could affect TRPV1 channels. Increased levels of TRPV1 receptors popped up in ME/CFS patients after exercise in one of the Light’s studies.

The TRPV1 channel is widely distributed in neuronal as well as non-neuronal tissues. In the peripheral nervous system, TRPV1 is highly expressed in a hangout place for herpesviruses – the dorsal root (DRG) ganglia which are implicated in pain sensitization. TRPV1 is over-expressed in several chronic pain conditions such as rheumatoid arthritis, osteoarthritis, bone cancer-induced pain and several neuropathies.

TRMP3

The lion’s share of polymorphisms were found in the TRPM3 gene. The most recently described and least well known TRP gene, TRMP3 was uncovered when it was found that the steroid pregnenolone sulfate activated it. Pregnenolone is the precursor to the mineralcorticoids, glucocorticoids, androgens and estrogens. It triggers the TRMP3 ion channels in the brain cells to release glutamate – an excitatory neurotransmitter.

TRPM3 ion channels have been implicated in inflammatory pain syndromes as well as rheumatoid arthritis, and the secretion of pro- inflammatory cytokines.

This channel’s ability to regulate insulin/glucose intake could impact metabolic functioning. Another intriguing function of this channel is to induce contractions of the smooth muscles than line the blood vessels and other areas. TRPM3 is not that well known yet, but it’s clear it plays an important role in detecting noxious stimuli in healthy and inflamed tissue and research is growing.

Wrapup

Sonya Marshall Gradisnuk leads the NCNED team that produced these findings. Such specific findings are both unusual and gratifying in ME/CFS. They suggest the researchers are on the right track. While the findings in this paper need to be replicated, for now, at least, there’s no muddiness – no need to strain at putting together some scenario that might work. There’s just the rather eye-popping finding that nine (almost ten) of the 13 gene alterations found significantly more often in ME/CFS patients in Australia were concentrated in just one of twenty-one genes examined.

It’s a bit unfortunate those genetic alterations occurred in one of the more recently described and less well known ion channels (TRPM3) but research into this ion channel is growing. (A recent study uncovered a substance able to open TRPM3 ion channels much more quickly than pregnenolone. That substance will be used to better understand TRPM3 ion channels. The finding indicated that TRPM3 activation contributes to neurogenic inflammation.)

What could be happening with these ion channels and ME/CFS? A tendency for them to genetically be set on a hair trigger could help explain the many and found overwhelming sensory sensation (pain, fatigue, problems with stimuli) found in the disorder. Drug companies are reportedly eagerly pursuing drugs that alter the function on these ion channels.

I'm still totally confused though and hoping you all can help me sort this out...

I found this article on how probenecid is a TRPA1 agonist too and it made me think about how Lerner often prescribed probenecid to potentiate antiviral drugs. Could it have been that it was working on this channel also? But the title says that probenecid desensitizes channel responses...and the abstract says that it activates TRPA1. It also seems like probenecid might increase intracellular calcium which would of course not be good. But I feel like I'm missing something. Help!

@Strike me lucky?

TRPA1 agonist activity of probenecid desensitizes channel responses: consequences for screening.
McClenaghan C, et al. Assay Drug Dev Technol. 2012.
Show full citation
Abstract
The transient receptor potential channel subtype A member 1 (TRPA1) is a nonselective cation channel widely viewed as having therapeutic potential, particularly for pain-related indications. Realization of this potential will require potent, selective modulators; however, currently the pharmacology of TRPA1 is poorly defined.

As TRPA1 is calcium permeable, calcium indicators offer a simple assay format for high-throughput screening. In this report, we show that probenecid, a uricosuric agent used experimentally in screening to increase loading of calcium-sensitive dyes, activates TRPA1. Prolonged probenecid incubation during the dye-loading process reduces agonist potency upon subsequent challenge. When Chinese Hamster Ovary (CHO)-hTRPA1 or STC-1 cells, which endogenously express TRPA1, were dye loaded in the presence of 2 mM probenecid TRPA1, agonists appeared less potent; EC(50) for allyl isothiocyante agonists in CHO-hTRPA1 was increased from 1.5±0.19 to 7.32±1.20 μM (P<0.01). No significant effect on antagonist potency was observed when using the agonist EC(80) concentration determined under the appropriate dye-loading conditions.

We suggest an alternative protocol for calcium imaging using another blocker of anion transport, sulfinpyrazone. This blocker significantly augments indicator dye loading and the screening window, but is not a TRPA1 agonist and has no effect on agonist potency.

 

[Hip]

Does anyone know if these polymorphisms found in ME/CFS patients increase intracellular calcium?

Because if these polymorphisms do increase the levels of calcium in cells, that may bring us back to the old RNase L cleavage story of ME/CFS.

Recall that RNase L is released inside a cell in order to fight intracellular viral infections. The RNase L enzyme destroys viral RNA as well as human RNA in the cell (so RNase L can have both good and bad effects).

However, it is known that in ME/CFS, the RNase L is chopped up (cleaved) into small fragments (called low molecular weight RNase L), and the degree of RNase L fragmentation in ME/CFS patients correlates with symptom severity.

Elastase, calpain and cathepsin G are all able to cleave RNase L, but Rich Van Konynenburg argued that calpain is the likely culprit responsible for this cleaving.

Now it just so happens that intracellular calcium activates calpain, so higher intracellular calcium means more activated calpain, which in turn may mean more chopped up RNase L.

Thus if ME/CFS patients have polymorphisms that increase intracellular calcium, that could explain their fragmented RNase L.