Abstract
BackgroundMyalgic 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.MethodsLive 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.ResultsThe 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).ConclusionTRPM3-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.
Highlights
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/Chronic fatigue syndrome (CFS)) is a serious disorder of unknown aetiology
We report, for the first time the significant reduction in Ca2+ influx via transient receptor potential melastatin 3 (TRPM3) in natural killer (NK) cells in Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients compared with healthy controls (HC) using Ca2+ imaging technique
Previous investigations have demonstrated TRPM3 channel dysfunction in isolated NK cells of ME/CFS patients compared with HC using the whole-cell patch clamp technique [10, 11]
Summary
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious disorder of unknown aetiology. In recent years evidence of transient receptor potential melastatin 3 (TRPM3) dysfunction supports the hypothesis that ME/CFS is potentially an ion channel disorder. 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. It has recently been reported that NTX restores impaired TRPM3 function in NK cells of ME/CFS patients. The activation of TRPM3 channels leads to a cascade of intracellular pathways to facilitate cell function in both excitable and nonexcitable cells [4]. The endogenous neurosteroid, pregnenolone sulfate (PregS) (EC50 = 12–32 μM) is commonly used in research to activate TRPM3 ion channel activity to induce an increase in intracellular C a2+ concentration [5] while ononetin (IC50 = 0.2–2 μM) rapidly and reversibly inhibits PregS-evoked ionic currents [6]. Changes in the function or activation of TRPM3 would result in changes to C a2+ and as a consequence impacts cell function
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