Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a seriously long-term and debilitating illness of unknown cause hallmarked by chronic pain and fatigue, memory and concentration impairment, and inflammation. ME/CFS hypothesis involves impaired Transient receptor potential melastatin 3...
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| Format: | Article |
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Frontiers Media S.A.
2019-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.02545/full |
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| author | Helene Cabanas Helene Cabanas Helene Cabanas Katsuhiko Muraki Katsuhiko Muraki Donald Staines Donald Staines Donald Staines Sonya Marshall-Gradisnik Sonya Marshall-Gradisnik Sonya Marshall-Gradisnik |
| author_facet | Helene Cabanas Helene Cabanas Helene Cabanas Katsuhiko Muraki Katsuhiko Muraki Donald Staines Donald Staines Donald Staines Sonya Marshall-Gradisnik Sonya Marshall-Gradisnik Sonya Marshall-Gradisnik |
| author_sort | Helene Cabanas |
| collection | DOAJ |
| description | Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a seriously long-term and debilitating illness of unknown cause hallmarked by chronic pain and fatigue, memory and concentration impairment, and inflammation. ME/CFS hypothesis involves impaired Transient receptor potential melastatin 3 (TRPM3) ion channel function, affecting calcium signaling and Natural killer (NK) cell functions. Currently, substances called opioids, agonists of mu (μ)-opioid receptors (μOR), are the strongest painkillers clinically available for people suffering from strong or long-lasting pain characteristic of ME/CFS. μOR have been reported to specifically inhibit TRPM3 and to be expressed in immune cells where they play an immunomodulatory and immunosuppressive role. Naltrexone hydrochloride (NTX) acts as an antagonist to the μOR thus negating the inhibitory function of this opioid receptor on TRPM3. Therefore, understanding the mechanism of action for NTX in regulating and modulating TRPM3 channel function in NK cells will provide important information for the development of effective therapeutic interventions for ME/CFS. Whole-cell patch-clamp technique was used to measure TRPM3 activity in Interleukin-2 (IL-2) stimulated and NTX-treated NK cells for 24 h on eight ME/CFS patients and 8 age- and sex-matched healthy controls, after modulation with a TRPM3-agonist, pregnenolone sulfate (PregS), NTX and a TRPM3-antagonist, ononetin. We confirmed impaired TRPM3 function in ME/CFS patients through electrophysiological investigations in IL-2 stimulated NK cells after modulation with PregS and ononetin. Importantly, TRPM3 channel activity was restored in IL-2 stimulated NK cells isolated from ME/CFS patients after incubation for 24 h with NTX. Moreover, we demonstrated that NTX does not act as an agonist by directly coupling on the TRPM3 ion channel gating. The opioid antagonist NTX has the potential to negate the inhibitory function of opioid receptors on TRPM3 in NK cells from ME/CFS patients, resulting in calcium signals remodeling, which will in turn affect cell functions, supporting the hypothesis that NTX may have potential for use as a treatment for ME/CFS. Our results demonstrate, for the first time, and based on novel patch clamp electrophysiology, potential pharmaco-therapeutic interventions in ME/CFS. |
| first_indexed | 2024-04-13T02:41:47Z |
| format | Article |
| id | doaj.art-f89f68dc9fa646599c989375e00a4fbd |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-13T02:41:47Z |
| publishDate | 2019-10-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-f89f68dc9fa646599c989375e00a4fbd2022-12-22T03:06:10ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-10-011010.3389/fimmu.2019.02545490373Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome PatientsHelene Cabanas0Helene Cabanas1Helene Cabanas2Katsuhiko Muraki3Katsuhiko Muraki4Donald Staines5Donald Staines6Donald Staines7Sonya Marshall-Gradisnik8Sonya Marshall-Gradisnik9Sonya Marshall-Gradisnik10School of Medical Science, Griffith University, Gold Coast, QLD, AustraliaThe National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, AustraliaConsortium Health International for Myalgic Encephalomyelitis, National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Gold Coast, QLD, AustraliaConsortium Health International for Myalgic Encephalomyelitis, National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Gold Coast, QLD, AustraliaLaboratory of Cellular Pharmacology, School of Pharmacy, Aichi-Gakuin University, Nagoya, JapanSchool of Medical Science, Griffith University, Gold Coast, QLD, AustraliaThe National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, AustraliaConsortium Health International for Myalgic Encephalomyelitis, National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Gold Coast, QLD, AustraliaSchool of Medical Science, Griffith University, Gold Coast, QLD, AustraliaThe National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, AustraliaConsortium Health International for Myalgic Encephalomyelitis, National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Gold Coast, QLD, AustraliaMyalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a seriously long-term and debilitating illness of unknown cause hallmarked by chronic pain and fatigue, memory and concentration impairment, and inflammation. ME/CFS hypothesis involves impaired Transient receptor potential melastatin 3 (TRPM3) ion channel function, affecting calcium signaling and Natural killer (NK) cell functions. Currently, substances called opioids, agonists of mu (μ)-opioid receptors (μOR), are the strongest painkillers clinically available for people suffering from strong or long-lasting pain characteristic of ME/CFS. μOR have been reported to specifically inhibit TRPM3 and to be expressed in immune cells where they play an immunomodulatory and immunosuppressive role. Naltrexone hydrochloride (NTX) acts as an antagonist to the μOR thus negating the inhibitory function of this opioid receptor on TRPM3. Therefore, understanding the mechanism of action for NTX in regulating and modulating TRPM3 channel function in NK cells will provide important information for the development of effective therapeutic interventions for ME/CFS. Whole-cell patch-clamp technique was used to measure TRPM3 activity in Interleukin-2 (IL-2) stimulated and NTX-treated NK cells for 24 h on eight ME/CFS patients and 8 age- and sex-matched healthy controls, after modulation with a TRPM3-agonist, pregnenolone sulfate (PregS), NTX and a TRPM3-antagonist, ononetin. We confirmed impaired TRPM3 function in ME/CFS patients through electrophysiological investigations in IL-2 stimulated NK cells after modulation with PregS and ononetin. Importantly, TRPM3 channel activity was restored in IL-2 stimulated NK cells isolated from ME/CFS patients after incubation for 24 h with NTX. Moreover, we demonstrated that NTX does not act as an agonist by directly coupling on the TRPM3 ion channel gating. The opioid antagonist NTX has the potential to negate the inhibitory function of opioid receptors on TRPM3 in NK cells from ME/CFS patients, resulting in calcium signals remodeling, which will in turn affect cell functions, supporting the hypothesis that NTX may have potential for use as a treatment for ME/CFS. Our results demonstrate, for the first time, and based on novel patch clamp electrophysiology, potential pharmaco-therapeutic interventions in ME/CFS.https://www.frontiersin.org/article/10.3389/fimmu.2019.02545/fulltransient receptor potential melastatin 3naltrexonecalciumopioid receptormyalgic encephalomyelitis/chronic fatigue syndromenatural killer cells |
| spellingShingle | Helene Cabanas Helene Cabanas Helene Cabanas Katsuhiko Muraki Katsuhiko Muraki Donald Staines Donald Staines Donald Staines Sonya Marshall-Gradisnik Sonya Marshall-Gradisnik Sonya Marshall-Gradisnik Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients Frontiers in Immunology transient receptor potential melastatin 3 naltrexone calcium opioid receptor myalgic encephalomyelitis/chronic fatigue syndrome natural killer cells |
| title | Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients |
| title_full | Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients |
| title_fullStr | Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients |
| title_full_unstemmed | Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients |
| title_short | Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients |
| title_sort | naltrexone restores impaired transient receptor potential melastatin 3 ion channel function in natural killer cells from myalgic encephalomyelitis chronic fatigue syndrome patients |
| topic | transient receptor potential melastatin 3 naltrexone calcium opioid receptor myalgic encephalomyelitis/chronic fatigue syndrome natural killer cells |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.02545/full |
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