calcium ion channels – American ME and CFS Society

People with ME/CFS have a consistent faulty cellular structure, new research confirms

Press Release:

A faulty ion channel function is a consistent biological feature of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), providing long-awaited validation for hundreds of thousands of Australians living with the debilitating illness.

The new Griffith University research found a crucial cellular structure responsible for calcium transport, the TRPM3 ion channel, was faulty in immune cells from people with ME/CFS.

The paper “Large-scale investigation confirms TRPM3 ion channel dysfunction in ME/CFS” has been published in Frontiers in Medicine.

Director and senior author, Professor Sonya Marshall-Gradisnik from Griffith’s National Center for Neuroimmunology and Emerging Diseases (NCNED), said the TRPM3 played an essential role in calcium transport into cells, regulating responses properly in the body, immune function, and maintaining normal cellular balance.

“When it fails, cells cannot function properly as calcium signaling is essential for healthy immune cell activity,” Professor Marshall-Gradisnik said.

“Our findings provide clear and definitive scientific evidence that TRPM3 ion channels are not working properly in people with ME/CFS.”

Read the rest of this press release HERE>>

Health-related quality of life in people with ME and Long Covid: A conversation with Breanna Weigel, Griffith University, Australia

By Dylan Murphy

In March 2024 the UN Disabilities Committee issued a damning report which stated that disabled people in the UK faced systemic violations of their human rights ranging from cuts to benefits to the lack of housing for disabled people. Fast forward to late February 2025 and the UN Economic and Cultural Committee issued a report on the UK which criticized the Labour government for its failures to reduce poverty and social inequality. Since then our government in its infinite wisdom has decided to slash £7 billion from disability benefits and is removing free bus passes from hundreds of thousands of disabled people on PIP.

On the ME front our government has engaged in endless gas lighting postponing the Department of Health care plan for ME several times. It claims that the care plan for ME will be published sometime in June just when it is due to announce major cuts to public spending which makes it very unlikely that it will put any resources into funding this plan.

In 2017 I put in a freedom of information request to the DWP which revealed that a third of pwME applying for PIP were having their applications turned down. The DWP is of course completely ignorant of the heavy disease burden of ME on those suffering with this wretched illness. It chooses to ignore the wealth of scientific evidence revealing the low quality of life outcomes for pwME.

In light of the above developments I came across a recent research paper, Health-related quality of life in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post COVID-19 Condition: A systematic review, by a group of scientists from the National Centre for Neuroimmunology and Emerging Diseases (NCNED) at Griffith University, Australia.

One of the co-authors of the above paper, Breanna Weigel, took time out from her busy schedule to talk to me about this important piece of research which may be of value to those pwME navigating the treacherous waters which are our current benefits system. It was such a pleasure to talk to a passionate young scientist who is so committed to the field of ME/Long Covid research. Breanna told me, “ It is a privilege to share these findings with the ME and Long COVID community, who have had an immeasurable impact on my growth as a researcher and my passion for making a difference for people who live with these chronic illness.’’

Breanna Weigel has five years’ experience working in the field of ME/CFS and Long COVID research at the National Centre for Neuroimmunology and Emerging Diseases (NCNED), Griffith University, Gold Coast, Australia. This month, Breanna will be submitting her PhD thesis, titled “Living with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID in Australia: An examination of illness experiences and healthcare policy”.

DM: How did you get involved in the field of ME research?

BW: Chronic illness has been an important part of my life and an area that I have wanted to work in for a long time. My Mum has lived with a chronic illness that has affected her life every day for the last 23 years. Seeing the extensive impacts that this had on my Mum, I was motivated to pursue a career that enabled me to contribute to helping people with chronic illness. I also developed a chronic illness four years ago, which considerably disrupted my life. However, my own lived experiences have provided me with additional insight that has informed my approach to research.

My involvement in ME research commenced in 2019 during my search for a supervisor for my Honours project. As I had a strong interest in public health and epidemiology, my program advisor shared with me the public health research that was being conducted at the National Centre for Neuroimmunology and Emerging Diseases (NCNED) and put me in contact with Prof Sonya Marshall-Gradisnik. It was then that I was introduced to the world of ME research.

I have continued to work with the NCNED over the last five years and I am presently finalising my PhD thesis, which highlights the lived experiences of people with ME and people with Post COVID-19 Condition (PCC). Throughout my early research career, I have had the invaluable opportunity to work directly with people who live with these conditions. Hearing their stories and experiences of living with ME or PCC has strengthened my motivation to make a difference for people who live with chronic illnesses that affect so many aspects of life.

DM: In the paper you co-authored, “Health-related quality of life in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post COVID-19 Condition: A systematic review”, you make the following observation: “people with ME/CFS (pwME/CFS) and people with PCC (pwPCC) are often precluded from accessing necessary disability and social support services. These unmet care needs exacerbate the existing illness burdens experienced by pwME/CFS and pwPCC.’’

This is a very timely and astute observation.

In October 2023 the Department of Health UK held a public consultation regarding its plans to improve the quality of life for people with ME, which admitted that people with ME face many difficulties accessing disability and social care services. Now we face huge cuts to disability benefits such as Personal Independence Payment (PIP), which many people with ME claim to help them with the extra costs of being disabled. Due to the fluctuating nature of the illness many people with ME have problems claiming disability benefits and accessing social care services.

Bearing this in mind can you explain the purpose of your systematic review?

BW: Unfortunately, many people with ME and people with PCC face similar barriers to receiving such necessary support in Australia. Based on results in my Honours and PhD research, approximately half of the people with ME who participated in these studies and were unable to work due to their illness were not receiving income support through the Disability Support Pension (DSP), which is our federally funded income assistance program here in Australia.

A primary barrier to accessing this necessary support for Australians who live with ME or PCC is the lack of recognition for these illnesses as real, physical disabilities in healthcare policy. The purpose of our recently published systematic review was, therefore, to elucidate that the profound impacts of ME and PCC on the health and functioning of people who live with these conditions warrant access to care and support services, such as the DSP.

The systematic review method enabled all relevant studies published worldwide to be included in the analysis. By examining all the existing relevant literature, this systematic review not only provided evidence that ME and PCC are associated with significantly lower quality of life when compared with healthy people, but also indicated that these findings are consistent across studies, countries and time.

DM: Sadly, pwME over many years have suffered from a dismissive and discriminatory attitude from many health professionals and media outlets with their illness being dismissed as psychosomatic in nature. Here in the UK, we still have some of the royal medical colleges maintaining that psychological therapies are an appropriate treatment for pwME. Many people with Long COVID are facing similar negative attitudes towards their illness. Based on the extensive research which you carried out for your systematic review, how would you characterize ME and Long COVID: Are they physical or psychological illnesses?

BW: The findings of our recent systematic review reiterate that ME and PCC are real, physical illnesses that are not psychogenic in nature. I use the term, “PCC”, here as our systematic review specifically examined publications documenting quality of life among people with persistent COVID-19-related symptoms for at least three months, which is consistent with the World Health Organization’s definition of “Post COVID-19 Condition” (PCC).

Importantly, the illness impact trends observed across the studies analyzed in our systematic review highlight that physical health and the ability to complete daily activities are consistently the most substantially impacted components of quality of life among people with ME and people with PCC. In addition, mental health was consistently the least impacted component of quality of life among these two cohorts. These findings affirm that, whilst living with an invisible and incurable chronic illness can have significant mental health repercussions, these impacts are secondary to and not causative of ME or PCC.

This conclusion is supported by the extensive literature documenting disruptions to cellular functioning among people with ME and people with PCC. This includes the world-first research from the NCNED. Laboratory-based studies from our Centre have consistently identified impaired TRPM3 calcium ion channel function among people * with ME and people with PCC, in which these impairments are absent in healthy people. * see footnote for explanation of this term.

DM: People with ME suffer from a multitude of symptoms which have a very debilitating and disabling impact on their lives. Can you explain the disabling impact of the illness on people with ME and its long-term impact on them? Do people with Long COVID suffer from the same issues?

BW: Our systematic review, for the first time, provides consistent evidence of the shared widespread impact of ME and PCC on the health and well being of people with these conditions. Overall health, as well as all individual aspects of health and functioning, are considerably poorer among pwME and pwPCC when compared with healthy people.

In conjunction with the results of two other studies that contribute to my PhD project (which were published in 2024 [1, 2]) and the NCNED’s laboratory findings [3, 4], the illness impact patterns observed in our systematic review indicate that the collection of post-COVID-19 sequelae (an after effect of a disease, condition, or injury) includes an illness presentation that is highly reminiscent of ME.

Combined with the post-viral nature of a considerable proportion of ME cases, this suggests that, after an episode of COVID-19, some people may experience the typical illness trajectory of people with ME. Hence, people who experience ME-like illness after COVID-19 may be at risk of long-term, complex chronic illness associated with widespread and debilitating symptoms, profound limitations on their ability to participate in daily, work and social life, and high healthcare needs.

DM: During the discussion section of your paper, you observe that pwME and people with Long COVID suffer from a comparable, profound level of disability. You note that “the illness presentation of ME/CFS and PCC poses a considerable barrier to completing physical tasks associated with daily living, …’’ Can you please explain this observation with examples from your research?

BW: The ability to participate in typical daily activities was consistently one of the most impacted components of health and functioning across the studies captured in our systematic review. In the context of the patient-reported outcome measures that were used to collect data in these studies, this refers to the ability to complete work both around the home and in relation to employment or study.

Such patient-reported outcome measures used by the studies included in our systematic review (and used in our studies at the NCNED) quantify quality of life and functioning across a range of scales. These include scales that consider overall health, as well as collections of more specific scales that focus on individual aspects of health. In terms of overall health, our research indicates that most people with ME/CFS and people with PCC have a functional status between 30% and 50% of total functioning. This is significantly lower than the level of functioning of healthy people, who typically return a score of (or close to) 100%.

Overall health status scores between 30% and 50% represent a considerable impact on the ability to complete daily activities, such as only being able to complete a limited number of tasks (like housework or grocery shopping) per day with adequate rest periods. However, people experiencing severe illness can return overall health status scores of 20% or 10%. People who return these considerably low scores may be mostly bed bound and unable to shower or eat independently.

The consistent finding that people with ME and people with PCC have a profoundly impaired ability to perform typical daily activities (including being able to continue employment) in our systematic review is critical in relation to guiding care and support access. As these impairments were repeatedly observed through the collection of data by validated and standardised patient-reported outcome measures, this provides evidence that ME and PCC are real, disabling conditions and must be considered eligible for care and support services, such as income assistance.”

DM: Your study is the first systematic review to capture and compare quality of life metrics for both pwME and people suffering from Long COVID. In your paper, you state “The present systematic review therefore serves to elucidate the pervasive impacts of ME/CFS and PCC on people who live with these conditions to inform and guide healthcare policy reform, as well as future research.” What recommendations would you suggest to public health agencies and governments to help pwME and Long COVID have a better quality of life?

BW: The co-production of healthcare policies and services with ME and PCC consumers will be an essential step in improving quality of life for people who live with these conditions. Importantly, care accessibility must be increased for these cohorts and the processes of accessing care must accommodate for the functional limitations of people who live with ME or PCC.

DM: I had the opportunity to further discuss the role of consumers’ lived illness experiences in shaping healthcare policy in my recent collaboration with the Deeble Institute for Health Policy Research, Australian Healthcare and Hospitals Association, which can be accessed via this link: https://doi.org/10.25916/b246-r560

BW: If anyone has any questions after reading the interview or would like to discuss our research in general, they are more than welcome to contact us at ncned@griffith.edu.au

References:
1. Weigel B, Eaton-Fitch N, Thapaliya K, & Marshall-Gradisnik SM. Illness presentation and quality of life in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post COVID-19 Condition: A pilot Australian cross-sectional study. Qual Life Res. 2024,33(9):2489–507. doi: 10.1007/s11136-024-03710-3.
2. Weigel B, Eaton-Fitch N, Thapaliya K, & Marshall-Gradisnik SM. A pilot cross-sectional investigation of symptom clusters and associations with patient-reported outcomes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post COVID-19 Condition. Qual Life Res. 2024,33(12):3229–43. doi: 10.1007/s11136-024-03794-x.
3. Martini Sasso E, Muraki K, Eaton-Fitch N, Smith P, Lesslar OL, Deed G, et al. Transient receptor potential melastatin 3 dysfunction in Post COVID-19 Condition and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients. Mol Med. 2022,28(1):98. doi: 10.1186/s10020-022-00528-y.
4. Martini Sasso E, Muraki K, Eaton-Fitch N, Smith P, Jeremijenko A, Griffin P, et al. Investigation into the restoration of TRPM3 ion channel activity in Post-COVID-19 Condition: A potential pharmacotherapeutic target. Front Immunol. 2024,15:1264702. doi: 10.3389/fimmu.2024.1264702.

Glossary

* What is TRPM3? Imagine TRPM3 as a tiny “gate” on the surface of cells. This gate specializes in allowing calcium ions (charged particles) to flow into the cell when triggered. Calcium acts like a messenger, telling the cell to perform specific tasks.

How Does It Work?

Triggers: The TRPM3 gate opens in response to certain signals, such as heat (like a body temperature rise) or specific molecules (like those released when you’re injured or when blood sugar is high). – Calcium’s Role: Once the gate opens, calcium rushes in, acting like a text message that alerts the cell to take action. This could mean sending a pain signal, releasing hormones, or adjusting to temperature changes.

1. Calcium Signaling & Cellular Stress: What’s Happening?

TRPM3 allows calcium to enter cells, which is critical for communication between nerves, muscles, and the immune system. In ME/CFS, abnormal calcium flow might disrupt this communication.

Impact: Too much calcium in cells (due to overactive TRPM3) could cause “cellular stress,” damaging mitochondria (the cell’s energy factories) or overstimulating nerves. This might explain the fatigue, muscle weakness, and “brain fog” seen in ME/CFS.

2. Pain Sensitivity & Nervous System Overdrive – What’s Happening?

TRPM3 helps nerves detect pain and temperature. If it’s hypersensitive, it might send constant “false alarms” to the brain.

Impact: This could contribute to chronic pain, allodynia (pain from light touch), or temperature intolerance (feeling too hot/cold) common in ME/CFS. It might also worsen “sensory overload,” where lights, sounds, or movement feel overwhelming.

3. Immune System & Inflammation – What’s Happening?

TRPM3 is activated by inflammatory molecules. In ME/CFS, chronic inflammation or immune dysfunction (e.g., after infections like Epstein-Barr virus) might keep TRPM3 stuck in the “on” position.

Impact: This could lead to a vicious cycle: inflammation → TRPM3 overactivity → more inflammation → worsened symptoms. Studies show ME/CFS patients often have abnormal immune cells (like natural killer cells), and TRPM3 defects in these cells might impair their ability to fight infections.

4. Energy Metabolism & Crashes – What’s Happening?

TRPM3 helps regulate insulin release and cellular energy. If it malfunctions, cells might struggle to manage glucose (sugar) for energy.

Impact: This could worsen energy crashes (post-exertional malaise) and contribute to the “dead battery” feeling in ME/CFS. Poor calcium regulation in muscles might also explain why even mild activity leads to severe fatigue.

5. The Bigger Picture: A Key Piece of the Puzzle?

ME/CFS is likely caused by a mix of genetic, immune, and environmental factors. TRPM3 dysfunction could be one piece of this puzzle. For example: – Genetic mutations in TRPM3 might make some people more prone to ME/CFS.

Viral infections or toxins could “break” TRPM3, triggering symptoms.

Overactive TRPM3 in the brain might disrupt sleep/wake cycles or hormone regulation.

Hope for Treatments? Researchers are exploring drugs that target TRPM3 to: ✅ Calm overactive channels (e.g., using blockers like primidone or certain antidepressants). ✅ Reduce inflammation linked to TRPM3 activation. ✅ Improve cellular energy by restoring calcium balance. However, this is still experimental—no treatments exist yet specifically for TRPM3 in ME/CFS.

Key Takeaway: TRPM3’s role in ME/CFS highlights how tiny cellular “gates” can have big impacts on fatigue, pain, and immune function. While more research is needed

Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence

Abstract:

Background: Recent studies provide strong evidence for a key role of skeletal muscle pathophysiology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In a 2021 review article on the pathophysiology of ME/CFS, we postulated that hypoperfusion and ischemia can result in excessive sodium and calcium overload in skeletal muscles of ME/CFS patients to cause mitochondrial damage. Since then, experimental evidence has been provided that supports this concept.

Methods: We collect, summarize and discuss the current state of knowledge for the key role of skeletal muscle pathophysiology. We try to explain which risk factors and mechanisms are responsible for a subgroup of patients with post COVID syndrome (PCS) to develop ME/CFS (PC-ME/CFS).

Results: Mitochondrial dysfunction is a long-held assumption to explain cardinal symptoms of ME/CFS. However, mitochondrial dysfunction could not be convincingly shown in leukocytes. By contrast, recent studies provide strong evidence for mitochondrial dysfunction in skeletal muscle tissue in ME/CFS. An electron microscopy study could directly show damage of mitochondria in skeletal muscle of ME/CFS patients with a preferential subsarcolemmal localization but not in PCS. Another study shows signs of skeletal muscle damage and regeneration in biopsies taken one day after exercise in PC-ME/CFS. The simultaneous presence of necroses and signs of regeneration supports the concept of repeated damage. Other studies correlated diminished hand grip strength (HGS) with symptom severity and prognosis. A MRI study showed that intracellular sodium in muscles of ME/CFS patients is elevated and that levels correlate inversely with HGS. This finding corroborates our concept of sodium and consecutive calcium overload as cause of muscular and mitochondrial damage caused by enhanced proton-sodium exchange due to anaerobic metabolism and diminished activity of the sodium-potassium-ATPase. The histological investigations in ME/CFS exclude ischemia by microvascular obstruction, viral presence or immune myositis. The only known exercise-induced mechanism of damage left is sodium induced calcium overload. If ionic disturbance and mitochondrial dysfunction is severe enough the patient may be captured in a vicious circle. This energy deficit is the most likely cause of exertional intolerance and post exertional malaise and is further aggravated by exertion.

Conclusion: Based on this pathomechanism, future treatment approaches should focus on normalizing the cause of ionic disbalance. Current treatment strategies targeting hypoperfusion have the potential to improve the dysfunction of ion transporters.

Source: Scheibenbogen C, Wirth KJ. Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence. J Cachexia Sarcopenia Muscle. 2025 Feb;16(1):e13669. doi: 10.1002/jcsm.13669. PMID: 39727052; PMCID: PMC11671797. https://pmc.ncbi.nlm.nih.gov/articles/PMC11671797/ (Full text)

Investigation into the restoration of TRPM3 ion channel activity in post-COVID-19 condition: a potential pharmacotherapeutic target

Abstract:

Introduction: Recently, we reported that post COVID-19 condition patients also have Transient Receptor Potential Melastatin 3 (TRPM3) ion channel dysfunction, a potential biomarker reported in natural killer (NK) cells from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients. As there is no universal treatment for post COVID-19 condition, knowledge of ME/CFS may provide advances to investigate therapeutic targets. Naltrexone hydrochloride (NTX) has been demonstrated to be beneficial as a pharmacological intervention for ME/CFS patients and experimental investigations have shown NTX restored TRPM3 function in NK cells. This research aimed to: i) validate impaired TRPM3 ion channel function in post COVID-19 condition patients compared with ME/CFS; and ii) investigate NTX effects on TRPM3 ion channel activity in post COVID-19 condition patients.

Methods: Whole-cell patch-clamp was performed to characterize TRPM3 ion channel activity in freshly isolated NK cells of post COVID-19 condition (N = 9; 40.56 ± 11.26 years), ME/CFS (N = 9; 39.33 ± 9.80 years) and healthy controls (HC) (N = 9; 45.22 ± 9.67 years). NTX effects were assessed on post COVID-19 condition (N = 9; 40.56 ± 11.26 years) and HC (N = 7; 45.43 ± 10.50 years) where NK cells were incubated for 24 hours in two protocols: treated with 200 µM NTX, or non-treated; TRPM3 channel function was assessed with patch-clamp protocol.

Results: This investigation confirmed impaired TRPM3 ion channel function in NK cells from post COVID-19 condition and ME/CFS patients. Importantly, PregS-induced TRPM3 currents were significantly restored in NTX-treated NK cells from post COVID-19 condition compared with HC. Furthermore, the sensitivity of NK cells to ononetin was not significantly different between post COVID-19 condition and HC after treatment with NTX.

Discussion: Our findings provide further evidence identifying similarities of TRPM3 ion channel dysfunction between ME/CFS and post COVID-19 condition patients. This study also reports, for the first time, TRPM3 ion channel activity was restored in NK cells isolated from post COVID-19 condition patients after in vitro treatment with NTX. The TRPM3 restoration consequently may re-establish TRPM3-dependent calcium (Ca²⁺) influx. This investigation proposes NTX as a potential therapeutic intervention and TRPM3 as a treatment biomarker for post COVID-19 condition.

Source: Etianne Martini Sasso, Katsuhiko Muraki, Natalie Eaton-Fitch, Peter Smith, Andrew Jeremijenko, Paul Griffin, Sonya Marshall-Gradisnik. Investigation into the restoration of TRPM3 ion channel activity in post-COVID-19 condition: a potential pharmacotherapeutic target. Front. Immunol., 02 May 2024; Sec. Multiple Sclerosis and Neuroimmunology; Volume 15 – 2024 | https://doi.org/10.3389/fimmu.2024.1264702. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1264702/full (Full text)

Altered TRPM7-Dependent Calcium Influx in Natural Killer Cells of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling multisystemic condition. The pathomechanism of ME/CFS remains unestablished; however, impaired natural killer (NK) cell cytotoxicity is a consistent feature of this condition. Calcium (Ca²⁺) is crucial for NK cell effector functions.

Growing research recognises Ca²⁺ signalling dysregulation in ME/CFS patients and implicates transient receptor potential ion channel dysfunction. TRPM7 (melastatin) was recently considered in the pathoaetiology of ME/CFS as it participates in several Ca²⁺-dependent processes that are central to NK cell cytotoxicity which may be compromised in ME/CFS. TRPM7-dependent Ca²⁺ influx was assessed in NK cells isolated from n = 9 ME/CFS patients and n = 9 age- and sex-matched healthy controls (HCs) using live cell fluorescent imaging techniques.

Slope (p < 0.05) was significantly reduced in ME/CFS patients compared with HCs following TRPM7 activation. Half-time of maximal response (p < 0.05) and amplitude (p < 0.001) were significantly reduced in the HCs compared with the ME/CFS patients following TRPM7 desensitisation.

Findings from this investigation suggest that TRPM7-dependent Ca²⁺ influx is reduced with agonism and increased with antagonism in ME/CFS patients relative to the age- and sex-matched HCs. The outcomes reported here potentially reflect TRPM3 dysfunction identified in this condition suggesting that ME/CFS is a TRP ion channelopathy.

Source: Du Preez S, Eaton-Fitch N, Smith PK, Marshall-Gradisnik S. Altered TRPM7-Dependent Calcium Influx in Natural Killer Cells of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Biomolecules. 2023; 13(7):1039. https://doi.org/10.3390/biom13071039 https://www.mdpi.com/2218-273X/13/7/1039 (Full text)

Impaired TRPM3-dependent calcium influx and restoration using Naltrexone in natural killer cells of myalgic encephalomyelitis/chronic fatigue syndrome patients

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious disorder of unknown aetiology. While the pathomechanism of ME/CFS remains elusive, reduced natural killer (NK) cell cytotoxic function is a consistent immunological feature. NK cell effector functions rely on long-term sustained calcium (Ca²⁺) influx. In recent years evidence of transient receptor potential melastatin 3 (TRPM3) dysfunction supports the hypothesis that ME/CFS is potentially an ion channel disorder. Specifically, reports of single nucleotide polymorphisms, low surface expression and impaired function of TRPM3 have been reported in NK cells of ME/CFS patients. It has been reported that mu (µ)-opioid receptor (µOR) agonists, known collectively as opioids, inhibit TRPM3. Naltrexone hydrochloride (NTX), a µOR antagonist, negates the inhibitory action of µOR on TRPM3 function. Importantly, it has recently been reported that NTX restores impaired TRPM3 function in NK cells of ME/CFS patients.

Methods: Live cell immunofluorescent imaging was used to measure TRPM3-dependent Ca²⁺ influx in NK cells isolated from n = 10 ME/CFS patients and n = 10 age- and sex-matched healthy controls (HC) following modulation with TRPM3-agonist, pregnenolone sulfate (PregS) and TRPM3-antaognist, ononetin. The effect of overnight (24 h) NTX in vitro treatment on TRPM3-dependent Ca²⁺ influx was determined.

Results: The amplitude (p < 0.0001) and half-time of Ca²⁺ response (p < 0.0001) was significantly reduced at baseline in NK cells of ME/CFS patients compared with HC. Overnight treatment of NK cells with NTX significantly improved TRPM3-dependent Ca²⁺ influx in ME/CFS patients. Specifically, there was no significance between HC and ME/CFS patients for half-time response, and the amplitude of Ca²⁺ influx was significantly increased in ME/CFS patients (p < 0.0001).

Conclusion: TRPM3-dependent Ca²⁺ influx was restored in ME/CFS patients following overnight treatment of isolated NK cells with NTX in vitro. Collectively, these findings validate that TRPM3 loss of function results in altered Ca²⁺ influx supporting the growing evidence that ME/CFS is a TRP ion channel disorder and that NTX provides a potential therapeutic intervention for ME/CFS.

Source: Eaton-Fitch N, Du Preez S, Cabanas H, Muraki K, Staines D, Marshall-Gradisnik S. Impaired TRPM3-dependent calcium influx and restoration using Naltrexone in natural killer cells of myalgic encephalomyelitis/chronic fatigue syndrome patients. J Transl Med. 2022 Feb 16;20(1):94. doi: 10.1186/s12967-022-03297-8. PMID: 35172836. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03297-8 (Full text)

Loss of Transient Receptor Potential Melastatin 3 ion channel function in natural killer cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients

Abstract:

BACKGROUND: Chronic Fatigue Syndrome (CFS)/ Myalgic Encephalomyelitis (ME) is a debilitating disorder that is accompanied by reduced cytotoxic activity in natural killer (NK) cells. NK cells are an essential innate immune cell, responsible for recognising and inducing apoptosis of tumour and virus infected cells. Calcium is an essential component in mediating this cellular function. Transient Receptor Potential Melastatin 3 (TRPM3) cation channels have an important regulatory role in mediating calcium influx to help maintain cellular homeostasis. Several single nucleotide polymorphisms have been reported in TRPM3 genes from isolated peripheral blood mononuclear cells, NK and B cells in patients with CFS/ME and have been proposed to correlate with illness presentation. Moreover, a significant reduction in both TRPM3 surface expression and intracellular calcium mobilisation in NK cells has been found in CFS/ME patients compared with healthy controls. Despite the functional importance of TRPM3, little is known about the ion channel function in NK cells and the epiphenomenon of CFS/ME. The objective of the present study was to characterise the TRPM3 ion channel function in NK cells from CFS/ME patients in comparison with healthy controls using whole cell patch-clamp techniques.

METHODS: NK cells were isolated from 12 age- and sex-matched healthy controls and CFS patients. Whole cell electrophysiology recording has been used to assess TRPM3 ion channel activity after modulation with pregnenolone sulfate and ononetin.

RESULTS: We report a significant reduction in amplitude of TRPM3 current after pregnenolone sulfate stimulation in isolated NK cells from CFS/ME patients compared with healthy controls. In addition, we found pregnenolone sulfate-evoked ionic currents through TRPM3 channels were significantly modulated by ononetin in isolated NK cells from healthy controls compared with CFS/ME patients.

CONCLUSIONS: TRPM3 activity is impaired in CFS/ME patients suggesting changes in intracellular Ca2+ concentration, which may impact NK cellular functions. This investigation further helps to understand the intracellular-mediated roles in NK cells and confirm the potential role of TRPM3 ion channels in the aetiology and pathomechanism of CFS/ME.

Source: Cabanas H, Muraki K, Eaton N, Balinas C, Staines D, Marshall-Gradisnik S. Loss of Transient Receptor Potential Melastatin 3 ion channel function in natural killer cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients. Mol Med. 2018 Aug 14;24(1):44. doi: 10.1186/s10020-018-0046-1.

New light shed on cause of chronic fatigue syndrome

New research findings may shed new 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 characterized 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.

Journal Reference: Sonya Marshall-Gradisnik, Donald Staines, Pete Smith, Bernd Nilius, Ekua Brenu, Sandra Ramos. Examination of Single Nucleotide Polymorphisms (SNPs) in Transient Receptor Potential (TRP) Ion Channels in Chronic Fatigue Syndrome Patients. Immunology and Immunogenetics Insights, 2015; 1 DOI: 10.4137/III.S25147

Source: Griffith University. “New light shed on cause of chronic fatigue syndrome.” ScienceDaily. ScienceDaily, 11 May 2015. https://www.sciencedaily.com/releases/2015/05/150511172755.htm

Single nucleotide polymorphisms and genotypes of transient receptor potential ion channel and acetylcholine receptor genes from isolated B lymphocytes in myalgic encephalomyelitis/chronic fatigue syndrome patients

Abstract:

OBJECTIVE: The pathomechanism of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is unknown; however, a small subgroup of patients has shown muscarinic antibody positivity and reduced symptom presentation following anti-CD20 intervention. Given the important roles of calcium (Ca2+) and acetylcholine (ACh) signalling in B cell activation and potential antibody development, we aimed to identify relevant single nucleotide polymorphisms (SNPs) and genotypes in isolated B cells from CFS/ME patients.

METHODS: A total of 11 CFS/ME patients (aged 31.82 ± 5.50 years) and 11 non-fatigued controls (aged 33.91 ± 5.06 years) were included. Flow cytometric protocols were used to determine B cell purity, followed by SNP and genotype analysis for 21 mammalian TRP ion channel genes and nine mammalian ACh receptor genes. SNP association and genotyping analysis were performed using ANOVA and PLINK analysis software.

RESULTS: Seventy-eight SNPs were identified in nicotinic and muscarinic acetylcholine receptor genes in the CFS/ME group, of which 35 were in mAChM3. The remaining SNPs were identified in nAChR delta (n = 12), nAChR alpha 9 (n = 5), TRPV2 (n = 7), TRPM3 (n = 4), TRPM4 (n = 1) mAChRM3 2 (n = 2), and mAChRM5 (n = 3) genes. Nine genotypes were identified from SNPs in TRPM3 (n = 1), TRPC6 (n = 1), mAChRM3 (n = 2), nAChR alpha 4 (n = 1), and nAChR beta 1 (n = 4) genes, and were located in introns and 3′ untranslated regions. Odds ratios for these specific genotypes ranged between 7.11 and 26.67 for CFS/ME compared with the non-fatigued control group.

CONCLUSION: This preliminary investigation identified a number of SNPs and genotypes in genes encoding TRP ion channels and AChRs from B cells in patients with CFS/ME. These may be involved in B cell functional changes, and suggest a role for Ca2+ dysregulation in AChR and TRP ion channel signalling in the pathomechanism of CFS/ME.

Source: Marshall-Gradisnik S, Johnston S, Chacko A, Nguyen T, Smith P, Staines D. Single nucleotide polymorphisms and genotypes of transient receptor potential ion channel and acetylcholine receptor genes from isolated B lymphocytes in myalgic encephalomyelitis/chronic fatigue syndrome patients. J Int Med Res. 2016 Nov 10. pii: 0300060516671622. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27834303

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

Abstract:

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 CD56dim CD16+ NK cells and CD56bright CD16dim/- 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 CD56bright CD16dim/- 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 CD56bright CD16dim/- NK cells showed a significant increase in Ca2+ flux in CFS/ME patients compared with HC. By comparison, unstimulated CD56dim CD16+ NK cells showed no significant difference in both Ca2+ flux and TRPM3 expression. PregS-stimulated CD56dim CD16+ NK cells increased TRPM3 expression significantly in CFS/ME, but this was not associated with a significant increase in Ca2+ flux.

Furthermore, TG-stimulated CD56dim CD16+ 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.

Source: Nguyen T, Johnston S, Clarke L, Smith P, Staines D, Marshall-Gradisnik S. Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channels. Clin Exp Immunol. 2017 Feb;187(2):284-293. doi: 10.1111/cei.12882. Epub 2016 Nov 23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217865/ (Full article)