Transient Receptor Potential Melastatin 3 (TRPM3) is an ion channel that plays a crucial role in regulating movement of certain ions (charged particles) across cell membranes. This ion movement is essential for various physiological processes, such as cell signalling, homeostasis (maintaining a stable internal environment), and responding to external stimuli such as heat.
TRPM3 is expressed in numerous tissues throughout the body, including the brain, spinal cord, retina, pituitary gland, kidneys, ovaries, sensory nerves, vascular smooth muscle, skin, and testes.
Two researchers in Germany recently reviewed the role of TRPM3 dysfunction in ME/CFS, and long COVID, and how low-dose naltrexone (LDN) can be used to combat this.
TRPM3 Dysfunction in ME/CFS
In individuals with ME/CFS, and long COVID, dysfunction of TRPM3 has been observed, particularly in natural killer (NK) cells – a type of white blood cell involved in immune responses. This dysfunction may play a role in the development of autoimmunity where the body’s immune system mistakenly attacks its own tissues.
TRPM3 dysfunction can be measured by assessing the decreased influx of calcium ions into cells. This disruption in calcium signalling could be a key factor in the disease mechanism of ME/CFS.
The Role of Low-Dose Naltrexone (LDN)
Naltrexone, particularly in low doses (LDN), has been shown through in vitro (typically test tube-based) and ex vivo (tests on living tissues in an external environment) studies to improve TRPM3 dysfunction in NK cells. This suggests the potential of LDN as a therapeutic agent for ME/CFS. LDN is sometimes prescribed off-label for ME/CFS, and long COVID and there have been anecdotal reports of clinical benefits. However, the drug is not licensed for use in ME/CFS or long COVID.
The researchers suggest that TRPM3 dysfunction is unlikely to be confined to NK cells alone. Instead, it may affect other tissues and organs, including small nerve fibres and the brain. Improvements in TRPM3 function in these areas could help explain the broader clinical benefits of LDN in ME/CFS.
Currently a double blind randomised clinical trial of LDN is being conducted in individuals with long COVID, with phase 2 due to be completed at the end of 2024.
Disease Mechanisms and Symptoms related to TRPM3
Mutations in TRPM3 can lead to either a gain-of-function (where the protein gains a new or enhanced activity) or a loss-of-function (where the protein loses its usual activity). Gain-of-function mutations in TRPM3 have been linked to various neurodevelopmental disorders, such as intellectual disability, epilepsy, musculoskeletal problems, altered pain perception, and also inherited eye conditions. In contrast, ME/CFS is the only known condition linked to a loss-of-function mutation in TRPM3.
This difference in TRPM3 mutation type in ME/CFS may have important implications for the development of targeted treatments. Although further research is needed to better understand these differences and their potential therapeutic significance.
TRPM3 dysfunction may also be implicated in certain characteristics of ME/CFS –
- Thermodysregulation (inability to regulate body temperature)
TRPM3 is involved in regulating body temperature, and individuals with ME/CFS often report issues with temperature control. While the exact connection is not yet fully understood, it suggests that TRPM3 dysfunction may contribute to this common symptom. - Nerve Fibre Degeneration
TRPM3 has also been implicated in nerve fibre degeneration. Could this potentially be linked to small fibre neuropathy? – A condition characterised by damage to small nerve fibres that many individuals with ME/CFS experience.
- Heightened sympathetic nervous system activity
TRPM3 dysfunction “may play a role in the hypervigilance and elevated sympathetic activity that are typical in ME/CFS and in skeletal muscle pathophysiology” which could potentially exacerbate symptoms of ME/CFS such as fatigue and PEM.
Conclusion and Future Directions
The researchers emphasise that investigating TRPM3 dysfunction in ME/CFS and long COVID is essential for advancing our understanding of these conditions. They suggest that TRPM3 dysfunction contributes to the immunological disturbances, skeletal muscle dysfunction, and neurological symptoms observed in these conditions. Exploring TRPM3 function in small nerve fibres and the brain, beyond just NK cells, may offer a more comprehensive explanation the clinical efficacy of LDN in ME/CFS. Further studies are needed to explore the broader implications of TRPM3 dysfunction and the potential for therapeutic targeting.
