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. 2022 Aug 19;28(1):98.
doi: 10.1186/s10020-022-00528-y.

Transient receptor potential melastatin 3 dysfunction in post COVID-19 condition and myalgic encephalomyelitis/chronic fatigue syndrome patients

Etianne Martini Sasso  1   2   3 , Katsuhiko Muraki  4   5 , Natalie Eaton-Fitch  6   4 , Peter Smith  4   7 , Olivia Ly Lesslar  8   9 , Gary Deed  10 , Sonya Marshall-Gradisnik  6   4
Affiliations

Transient receptor potential melastatin 3 dysfunction in post COVID-19 condition and myalgic encephalomyelitis/chronic fatigue syndrome patients

Etianne Martini Sasso et al. Mol Med. .

Abstract

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe multisystemic condition associated with post-infectious onset, impaired natural killer (NK) cell cytotoxicity and impaired ion channel function, namely Transient Receptor Potential Melastatin 3 (TRPM3). Long-term effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has resulted in neurocognitive, immunological, gastrointestinal, and cardiovascular manifestations recently recognised as post coronavirus disease 2019 (COVID-19) condition. The symptomatology of ME/CFS overlaps significantly with post COVID-19; therefore, this research aimed to investigate TRPM3 ion channel function in post COVID-19 condition patients.

Methods: Whole-cell patch-clamp technique was used to measure TRPM3 ion channel activity in isolated NK cells of N = 5 ME/CFS patients, N = 5 post COVID-19 patients, and N = 5 healthy controls (HC). The TRPM3 agonist, pregnenolone sulfate (PregS) was used to activate TRPM3 function, while ononetin was used as a TRPM3 antagonist.

Results: As reported in previous research, PregS-induced TRPM3 currents were significantly reduced in ME/CFS patients compared with HC (p = 0.0048). PregS-induced TRPM3 amplitude was significantly reduced in post COVID-19 condition compared with HC (p = 0.0039). Importantly, no significant difference was reported in ME/CFS patients compared with post COVID-19 condition as PregS-induced TRPM3 currents of post COVID-19 condition patients were similar of ME/CFS patients currents (p > 0.9999). Isolated NK cells from post COVID-19 condition and ME/CFS patients were resistant to ononetin and differed significantly with HC (p < 0.0001).

Conclusion: The results of this investigation suggest that post COVID-19 condition patients may have impaired TRPM3 ion channel function and provide further evidence regarding the similarities between post COVID-19 condition and ME/CFS. Impaired TRPM3 channel activity in post COVID-19 condition patients suggest impaired ion mobilisation which may consequently impede cell function resulting in chronic post-infectious symptoms. Further investigation into TRPM3 function may elucidate the pathomechanism, provide a diagnostic and therapeutic target for post COVID-19 condition patients and commonalities with ME/CFS patients.

Keywords: Coronavirus; Myalgic encephalomyelitis/chronic fatigue syndrome; Natural killer cells; Post COVID-19 condition; SARS-CoV-2; Transient receptor potential melastatin 3; Whole-cell patch clamp electrophysiology.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
TRPM3 activity after PregS stimulation. Data were obtained under whole-cell patch-clamp conditions. Comparing all groups, amplitude of ionic current after PregS stimulation we found a significant difference (p = 0.0010). A A representative time-series of current amplitude at + 100 mV and − 100 mV showing the effect of 100 μΜ PregS on ionic currents in isolated NK cells from HC. B I–V before and after PregS stimulation in a cell corresponding with (A). C A representative time-series of current amplitude at + 100 mV and − 100 mV showing the effect of 100 μΜ PregS on ionic currents in isolated NK cells from ME/CFS patients. D. I–V before and after PregS stimulation in a cell as shown in (C). E A representative time-series of current amplitude at + 100 mV and − 100 mV showing the effect of 100 μΜ PregS on ionic currents in isolated NK cells from post COVID-19 condition patient. F I–V before and after PregS stimulation in a cell corresponding with (E). G Bar graphs representing TRPM3 current amplitude at + 100 mV after stimulation with 100 μΜ PregS in HC patients (N = 5; n = 34) compared with post COVID-19 condition patients (N = 5; n = 38) and ME/CFS patients (N = 5; n = 26). TRPM3 currents were determined as a change in amplitude from baseline to PregS induced peak as represented in time-series graphs. I–V curves were used to identify an outward rectification typical of TRPM3. N refers to number of participants and n to number of records analysed. Data are represented as mean ± SEM. HC healthy control, ME/CFS myalgic encephalomyelitis/chronic fatigue syndrome
Fig. 2
Fig. 2
TRPM3 activity after ononetin modulation. Data were obtained under whole-cell patch-clamp conditions. A A representative time-series of current amplitude at + 100 mV and − 100 mV showing the effect of 10 μΜ ononetin on ionic currents in the presence of PregS in isolated NK cells from HC. B I–V before and after application of ononetin in a cell as shown in (A). C Scatter plots representing change of each current amplitude before and after application of ononetin in presence of PregS in all NK cells from HC. D A representative time-series of current amplitude at + 100 mV and − 100 mV showing the effect of 10 μΜ ononetin on ionic currents in the presence of PregS in isolated NK cells ME/CFS patients. E I–V before and after application of ononetin in a cell as shown in (D). F Scatter plots representing change of each current amplitude before and after application of ononetin in presence of PregS in all NK cells from ME/CFS. G A representative time-series of current amplitude at + 100 mV and − 100 mV showing the effect of 10 μΜ ononetin on ionic currents in the presence of PregS in isolated NK cells from post COVID-19 condition. H I–V before and after application of ononetin in a cell as shown in (G). I Scatter plots representing change of each current amplitude before and after application of ononetin in presence of PregS in all NK cells from post COVID-19 condition. Each cell represented as red lines indicate cells sensitive to ononetin as a reduction in amplitude was recorded. HC (N = 5; n = 29), post COVID-19 condition (N = 5; n = 27), and ME/CFS (N = 5; n = 23). N to number of participants and n to number of records analysed. HC healthy controls, ME/CFS myalgic encephalomyelitis/chronic fatigue syndrome
Fig. 3
Fig. 3
Summary TRPM3 activity after ononetin modulation. Data were obtained under whole-cell patch-clamp conditions. Table summarizing data for sensitive and insensitive cells to 10 μΜ ononetin, (A) absolute number and (B) percentage. C Bar graphs representing sensitive and insensitive cells to 10 μΜ ononetin, HC patients (N = 5; n = 29) compared with post COVID-19 condition patients (N = 5; n = 27) and ME/CFS patients (N = 5; n = 23). Data are analysed using Fisher’s exact test. N refers to number of participants and n to number of records analysed. HC healthy controls, ME/CFS myalgic encephalomyelitis/chronic fatigue syndrome
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