ORIGINAL RESEARCH article
Front. Mol. Biosci.
Sec. Molecular Diagnostics and Therapeutics
Volume 12 - 2025 | doi: 10.3389/fmolb.2025.1582967
Low-Dose Naltrexone restored TRPM3 ion channel function in Natural Killer cells from long COVID patients
Provisionally accepted
Etianne Martini Sasso1,2,3*
Natalie Eaton-Fitch1,2
Peter Kenneth Smith2,4
Muraki Katsuhiko2,5
Sonya Marshall-Gradisnik1,2- 1National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Gold Coast, Australia
- 2Consortium Health International for Myalgic Encephalomyelitis, National Centre for Neuroimmunology and Emerging Diseases, Gold Coast, Australia
- 3School of Pharmacy and Medical Sciences, Griffith University, Gold Coast, Queensland, Australia
- 4Queensland Allergy Services, Gold Coast, Australia
- 5Laboratory of Cellular Pharmacology, School of Pharmacy, Aichi-Gakuin University, Nagoya, Aichi, Japan
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Long COVID is a multisystemic condition that includes neurocognitive, immunological, gastrointestinal and cardiovascular manifestations, independent of the severity or duration of SARS-CoV-2 acute infection. Dysfunctional Transient Receptor Potential Melastatin 3 (TRPM3) ion channels are associated with long COVID pathophysiology due to a reduced calcium (Ca 2+ ) influx, negatively impacting cellular processes in diverse systems. Accumulating evidence suggests the potential therapeutic benefits of low-dose naltrexone (LDN) for people suffering from long COVID. Our study aimed to investigate treatment efficacy with LDN in restoring the TRPM3 ion channel function in natural killer (NK) cells from long COVID patients. NK cells were isolated from nine people with long COVID, nine healthy controls and nine people with long COVID taking LDN (3 -4.5 mg/day). Electrophysiological experiments were used to assess TRPM3 ion channel functions modulated with pregnenolone sulfate and ononetin. The findings from this current research are the first to demonstrate that long COVID patients treated with LDN have restored TRPM3 ion channel function and also validate previous findings of TRPM3 ion channel dysfunction in NK cells from people with long COVID not on treatment. There was no significant difference in TRPM3 currents between long COVID patients taking LDN and HC in either PregS-induced current amplitude (p>0.9999) or resistance to ononetin (p>0.9999). Overall, our findings support LDN as a potentially beneficial treatment for long COVID patients by restoring TRPM3 ion channel function and reestablishing adequate Ca 2+ influx for homeostatic cellular processes to occur.
Keywords: Calcium, TRP ion channels, TRPM3, Long Covid, Low-dose naltrexone (LDN), Transient Receptor Potential Melastatin 3 (TRPM3)
Received: 25 Feb 2025; Accepted: 08 Apr 2025.
Copyright: © 2025 Sasso, Eaton-Fitch, Smith, Katsuhiko and Marshall-Gradisnik. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Etianne Martini Sasso, National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Gold Coast, Australia
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