Abstract
BackgroundChronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) is a complex multifactorial disorder of unknown cause having multi-system manifestations. Although the aetiology of CFS/ME remains elusive, immunological dysfunction and more particularly reduced cytotoxic activity in natural killer (NK) cells is the most consistent laboratory finding. The Transient Receptor Potential (TRP) superfamily of cation channels play a pivotal role in the pathophysiology of immune diseases and are therefore potential therapeutic targets. We have previously identified single nucleotide polymorphisms in TRP genes in peripheral NK cells from CFS/ME patients. We have also described biochemical pathway changes and calcium signaling perturbations in NK cells from CFS/ME patients. Notably, we have previously reported a decrease of TRP cation channel subfamily melastatin member 3 (TRPM3) function in NK cells isolated from CFS/ME patients compared with healthy controls after modulation with pregnenolone sulfate and ononetin using a patch-clamp technique. In the present study, we aim to confirm the previous results describing an impaired TRPM3 activity in a new cohort of CFS/ME patients using a whole cell patch-clamp technique after modulation with reversible TRPM3 agonists, pregnenolone sulfate and nifedipine, and an effective TRPM3 antagonist, ononetin. Indeed, no formal research has commented on using pregnenolone sulfate or nifedipine to treat CFS/ME patients while there is evidence that clinicians prescribe calcium channel blockers to improve different symptoms.MethodsWhole-cell patch-clamp technique was used to measure TRPM3 activity in isolated NK cells from twelve age- and sex-matched healthy controls and CFS/ME patients, after activation with pregnenolone sulfate and nifedipine and inhibition with ononetin.ResultsWe confirmed a significant reduction in amplitude of TRPM3 currents after pregnenolone sulfate stimulation in isolated NK cells from another cohort of CFS/ME patients compared with healthy controls. The pregnenolone sulfate-evoked ionic currents through TRPM3 channels were again significantly modulated by ononetin in isolated NK cells from healthy controls compared with CFS/ME patients. In addition, we used nifedipine, another reversible TRPM3 agonist to support the previous findings and found similar results confirming a significant loss of the TRPM3 channel activity in CFS/ME patients.ConclusionsImpaired TRPM3 activity was validated in NK cells isolated from CFS/ME patients using different pharmacological tools and whole-cell patch-clamp technique as the gold standard for ion channel research. This investigation further helps to establish TRPM3 channels as a prognostic marker and/ or a potential therapeutic target for CFS/ME.
Highlights
Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) is a complex multifactorial disorder of unknown cause having multi-system manifestations
Impaired TRP cation channel subfamily melastatin member 3 (TRPM3) activity was validated in natural killer (NK) cells isolated from CFS/ME patients using different pharmacological tools and whole-cell patch-clamp technique as the gold standard for ion channel research
Whole-cell patch-clamp technique was used as a method to measure endogenous TRPM3 activity in isolated NK cells from healthy controls (HC) and CFS/ME patients, enabling the ion channel current recordings under voltage-clamp conditions and observation of the shape of the TRPM3 current–voltage relationship (I–V)
Summary
Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) is a complex multifactorial disorder of unknown cause having multi-system manifestations. Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) is a complex multi-faceted illness characterized by persistent, debilitating fatigue that is unrelieved by rest (Fukuda et al, 1994) This is accompanied by a variety of other adverse symptoms including: cognitive, muscular, joint, gastrointestinal, neurological and cardiovascular impairments (Carruthers et al, 2011). The Fukuda case definition (or Centers for Disease Control and Prevention (CDC) criteria (1994)) was the first set of frameworks established that are widely used to define CFS/ME populations both in research and clinical practice (Fukuda et al, 1994) This definition has been considered too broad in its symptoms requirements for a definite diagnosis (Johnston et al, 2013). More specific frameworks such as the Canadian Consensus Criteria (CCC) (2003) and International Case Criteria (ICC) (2011) have been developed to improve case identification (Carruthers et al, 2011)
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