Impaired TRPM3-dependent calcium influx and restoration using Naltrexone in natural killer cells of myalgic encephalomyeli...(Eaton-Fitch et al, 2022)

Consul

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Impaired TRPM3-dependent calcium influx and restoration using Naltrexone in natural killer cells of myalgic encephalomyelitis/chronic fatigue syndrome patients (Eaton-Fitch et al, 2022)

Authors:
Natalie Eaton-Fitch
Stanley Du Preez
Hélène Cabanas
Katsuhiko Muraki
Donald Staines
Sonya Marshall-Gradisnik

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.

The study: https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03297-8
 
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Consul

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I don’t understand why other groups have been unable to replicate this
Maybe nobody tried, idk.

But this disease is so odd, ppl are using that drug and the success rate doesnt appear to be too impressive from what i understand. Why is it not working.
 
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But this disease is so odd, ppl are using that drug and the success rate doesnt appear to be too impressive from what i understand. Why is it not working.
Its helped me.....but pinning down how exactly and what exactly has been hard to articulate.

It reduces some inflammatory symptoms I get...swelling up. The swelling starts up when I run out. I have run out a couple of times for like 5 days and 10 days. And I notice I"m doing worse. However, other things are going on when I ran out..(I'm not home, thats why I ran out)

I'd have to stop taking it and subject myself to some careful N=1 review to pin this down.
 

pattismith

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Maybe nobody tried, idk.

But this disease is so odd, ppl are using that drug and the success rate doesnt appear to be too impressive from what i understand. Why is it not working.
Naltrexone is used with low dose most of the time, maybe higher dosage is necessary to achieve TRPM3 restoration, I don't know.