Paroxetine suppresses recombinant human P2X7 responses.
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.
Sydney Medical School Nepean, University of Sydney, Nepean Hospital, Level 5 South Block, Derby Street, Penrith, NSW, 2750, Australia.
Phuong
P
Dao-Ung
Sydney Medical School Nepean, University of Sydney, Nepean Hospital, Level 5 South Block, Derby Street, Penrith, NSW, 2750, Australia.
Kristen K
KK
Skarratt
Sydney Medical School Nepean, University of Sydney, Nepean Hospital, Level 5 South Block, Derby Street, Penrith, NSW, 2750, Australia.
Stephen J
SJ
Fuller
Sydney Medical School Nepean, University of Sydney, Nepean Hospital, Level 5 South Block, Derby Street, Penrith, NSW, 2750, Australia. l.stokes@uea.ac.uk.|School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK. l.stokes@uea.ac.uk.
Leanne
L
Stokes
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology; D002997:Clomipramine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000494:pharmacology; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D017374:Paroxetine / Q000494:pharmacology*; D058911:Purinergic P2X Receptor Agonists / Q000494:pharmacology; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology*; D051381:Rats; D058486:Receptors, Purinergic P2X7 / Q000187:drug effects*; D011994:Recombinant Proteins / Q000187:drug effects; D014268:Trifluoperazine / Q000494:pharmacology
D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D014150:Antipsychotic Agents; C508585:IL1B protein, human; D053583:Interleukin-1beta; D018950:Lipopolysaccharide Receptors; C546468:P2RX7 protein, human; D058911:Purinergic P2X Receptor Agonists; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D011994:Recombinant Proteins; D005473:Fluoxetine; D014268:Trifluoperazine; D017374:Paroxetine; D002997:Clomipramine
ATP; Antidepressant; Fluoxetine; Interleukin 1β; P2X7; Paroxetine; Trifluoperazine