Impaired TRPM3-dependent calcium influx and restoration using Naltrexone in natural killer cells of [ME/CFS], 2022, Eaton-Fitch et al

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.

Open access, https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03297-8

 

I believe the "non-selective" means that it also allows other cations to pass. Cations include sodium, potassium, magnesium, calcium and others.

TRPM3 is most prominently expressed in the kidney with lower expression levels in the central and peripheral nervous systems, testis, and retina.

Do we know if TRPM3 in ME/CFS is altered in other places in the body than immune cells?

TRPM3 is activated by hypo-osmolality. Given the expression of TRPM3 in the kidneys, could TRPM3 dysfunction affect blood volume regulation?

Given the non-selective nature of TRPM3, would a dysfunction of this ion channel have effects that can resemble those of other ion channel disorders affecting the same tissues?

 

I'd take the hypothesis more seriously if LDN was more widely reported as an effective treatment for ME symptoms. For me it was wonderful for blocking my neurologically-perceived aches, but it did nothing else for my other ME symptoms. It doesn't matter how nice the hypothesis sounds, or how nice the numbers look in in vitro experiments; if taking LDN doesn't treat actual patients, it fails the real-world test.

 

Thats my concern as well. NCNED claim that TRPM3 dysfunction is the cause of ME/CFS, and that naltrexone repairs it, but we know that anecdotally LDN is very hit and miss. It helps some, doesn’t help others, makes yet others worse. I’ve not heard anyone report that naltrexone was curative for them. I understand that drug performance is very different in in vitro vs in vivo contexts, but you’d still expect that naltrexone would be more effective for more patients than it appears to be if it is indeed fixing the main underlying issue.