Paroxetine suppresses recombinant human P2X7 responses
Open accessAbstract
P2X7 receptor (P2X7) activity may link inflammation to depressive disorders. Genetic variants of human P2X7 have been linked with major depression and bipolar disorders, and the P2X7 knockout mouse has been shown to exhibit anti-depressive-like behaviour. P2X7 is an ATP-gated ion channel and is a major regulator of the pro-inflammatory cytokine interleukin 1β (IL-1β) secretion from monocytes and microglia. We hypothesised that antidepressants may elicit their mood enhancing effects in part via modulating P2X7 activity and reducing inflammatory responses. In this study, we determined whether common psychoactive drugs could affect recombinant and native human P2X7 responses in vitro. Common antidepressants demonstrated opposing effects on human P2X7-mediated responses; paroxetine inhibited while fluoxetine and clomipramine mildly potentiated ATP-induced dye uptake in HEK-293 cells stably expressing recombinant human P2X7. Paroxetine inhibited dye uptake mediated by human P2X7 in a concentration-dependent manner with an IC(50) of 24 μM and significantly reduces ATP-induced inward currents. We confirmed that trifluoperazine hydrochloride suppressed human P2X7 responses (IC(50) of 6.4 μM). Both paroxetine and trifluoperazine did not inhibit rodent P2X7 responses, and mutation of a known residue (F 95L) did not alter the effect of either drug, suggesting neither drug binds at this site. Finally, we demonstrate that P2X7-induced IL-1β secretion from lipopolysaccharide (LPS)-primed human CD14(+) monocytes was suppressed with trifluoperazine and paroxetine.
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The activity of P2X7R can be selectively modulated by different antidepressant drugs.
“These results suggest that the activity of the P2X7R can be selectively modulated by different antidepressants drugs, pointing to unknown mechanisms by which these drugs may exert their therapeutic and/or side effects.”
From P2X7 Receptor Signaling in Stress and Depression (2019) · cites this paper as [79]
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The P2X7 Receptor: Central Hub of Brain Diseases
Andrejew, R., Oliveira-Giacomelli, Á., Ribeiro, D. E., Glaser, T., Arnaud-Sampaio, V. F., Lameu, C., & Ulrich, H. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.00124 · Cited by 162 · see citing works
P2X7 Receptor Signaling in Stress and Depression
Ribeiro, D. E., Roncalho, A. L., Glaser, T., Ulrich, H., Wegener, G., & Joca, S. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20112778 · Cited by 129 · see citing works
Yue, N., Li, B., Yang, L., Han, Q.-Q., Huang, H.-J., Wang, Y.-L., Wang, J., Yu, R., Wu, G.-C., Liu, Q., et al. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00149 · Cited by 100 · see citing works
- Authors
- Dao-Ung, P., Skarratt, K. K., Fuller, S. J., & Stokes, L.
- Affiliations
- The University of Sydney (AU)
- University of East Anglia (GB)
- Corresponding author
- Stokes, Leanne
- Venue
- Purinergic Signalling
- Published
- 2015-09-05
- Volume
- 11
- Issue
- 4
- Pages
- 481-490
- ISSN
- 1573-9538 (ISSN-L)
- 1573-9546
- PMC
- PMC4648795
- OpenAlex
- W1674357349
- Cited by
- 29
- References
- 52
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 5 · 2022: 1 · 2021: 5 · 2020: 3 · 2019: 4 · 2018: 1 · 2017: 2 · 2016: 2
- FWCI
- 1.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Purinergic Signalling (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Funders
- University of Wollongong
- RMIT University
- Medical Research Council
- National Health and Medical Research Council (632687)
- Sydney Medical School
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- P2X7 receptor, paroxetine, trifluoperazine, antidepressants, fluoxetine, clomipramine, interleukin-1β secretion, ATP-gated ion channels, inflammation and depression, CD14+ monocytes, lipopolysaccharide, drug binding sites
- MeSH terms
- Animals, Antidepressive Agents, Tricyclic, Clomipramine, Dose-Response Relationship, Drug, Fluoxetine, Humans, Monocytes, Recombinant Proteins, Antipsychotic Agents, Trifluoperazine, Paroxetine, Antidepressive Agents, Second-Generation, Lipopolysaccharide Receptors, Mice, Rats, Interleukin-1beta, Receptors, Purinergic P2X7, Purinergic P2X Receptor Agonists, Purinergic P2X Receptor Antagonists
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