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Open Access 01-12-2022 | Naltrexone | Research

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

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

Published in: Journal of Translational Medicine | Issue 1/2022

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.

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Title: Impaired TRPM3-dependent calcium influx and restoration using Naltrexone in natural killer cells of myalgic encephalomyelitis/chronic fatigue syndrome patients
Authors: Natalie Eaton-Fitch
Stanley Du Preez
Hélène Cabanas
Katsuhiko Muraki
Donald Staines
Sonya Marshall-Gradisnik
Publication date: 01-12-2022
Publisher: BioMed Central
Keywords: Naltrexone
Fatigue
Published in: Journal of Translational Medicine / Issue 1/2022
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-022-03297-8

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