P2X7 Receptor: A Potential Therapeutic Target for Depression?

Deussing, Jan M.; Arzt, Eduardo

doi:10.1016/j.molmed.2018.07.005

Cited by 97Adenosine and Purinergic SignalingTryptophan and brain disordersTreatment of Major Depression

P2X7 Receptor: A Potential Therapeutic Target for Depression?

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Deussing, Jan M., Arzt, Eduardo·2018·Trends in Molecular Medicine

DOI 10.1016/j.molmed.2018.07.005

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Abstract

Depression is a prime contributor to global disease burden with 300 million affected patients worldwide. The persistent lack of progress with regards to pharmacotherapy stands in stark contrast to the pandemic magnitude of the disease. Alterations of inflammatory pathways in depressed patients, including altered circulating pro-inflammatory cytokines, have been put forward as a potential pathophysiological mechanism. The P2X7 receptor (P2X7R) plays an important role regulating the release of interleukin-1β and other cytokines. Comprehensive investigation of the P2X7R Gln460Arg missense mutation (rs2230912), which has been associated with major depression and bipolar disorder, has substantially contributed to validate P2X7R as a potential genetic risk factor. We propose that P2X7R is a putative target with good prospects for therapeutic intervention in depressive disorders.

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Neuroinflammation and increased levels of ATP are observed in neuropsychiatry disorders, supposedly correlated with P2X7 receptor activation.
“Neuroinflammation and increased levels of ATP are observed in neuropsychiatry disorders, supposedly correlated with P2X7 receptor activation [118, 145].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [145]
P2X7R has been suggested as a putative target for therapeutic intervention in mood disorders.
“Among the purinergic receptors, the P2X7R has been suggested as a putative target for therapeutic intervention in mood disorders [33] (Figure 2).”
From P2X7 Receptor Signaling in Stress and Depression (2019) · cites this paper as [33]

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Significance of risk polymorphisms for depression depends on stress exposure
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The P2RX7 polymorphism rs2230912 is associated with depression: A meta-analysis
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Heterozygosity for the mood disorder-associated variant Gln460Arg alters P2X7 receptor function and sleep quality
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Understanding the role of P2X7 in affective disorders—are glial cells the major players?
Stokes, L., Spencer, S. J., & Jenkins, T. A. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00258 · Cited by 58 · see citing works
Associations between depression severity and purinergic receptor P2RX7 gene polymorphisms
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Variation in P2RX7 candidate gene (rs2230912) is not associated with bipolar I disorder and unipolar major depression in four European samples
Grigoroiu‐Serbânescu, M., Herms, S., Mühleisen, T. W., Georgi, A., Diaconu, C. C., Strohmaier, J., Czerski, P. M., Hauser, J., Leszczyńska-Rodziewicz, A., Jamra, R. A., et al. (2009) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30952 · Cited by 55 · see citing works
Synthesis and in vitro characterization of a P2X7 radioligand [123I]TZ6019 and its response to neuroinflammation in a mouse model of Alzheimer disease
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Lymphocytes from P2X7-deficient mice exhibit enhanced P2X7 responses
Taylor, S. R. J., González–Begne, M., Sojka, D. K., Richardson, J. C., Sheardown, S. A., Harrison, S. M., Pusey, C. D., Tam, F. W. K., & Elliott, J. I. (2009) · Journal of Leukocyte Biology · doi:10.1189/jlb.0408251 · Cited by 49 · see citing works
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Lack of Association of P2RX7 Gene rs2230912 Polymorphism with Mood Disorders: A Meta-Analysis
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P2RX7: Expression Responds to Sleep Deprivation and Associates with Rapid Cycling in Bipolar Disorder Type 1
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Case-control association study of 65 candidate genes revealed a possible association of a SNP of HTR5A to be a factor susceptible to bipolar disease in Bulgarian population
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Chronic stress induces prolonged suppression of the P2X7 receptor within multiple regions of the hippocampus: A cumulative threshold spectra analysis
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Co-Expression of Wild-Type P2X7R with Gln460Arg Variant Alters Receptor Function
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Targeted mutagenesis tools for modelling psychiatric disorders
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Functional significance of P2RX7 polymorphisms associated with affective mood disorders
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From purines to purinergic signalling: molecular functions and human diseases
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Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology
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P2X7 Receptors Amplify CNS Damage in Neurodegenerative Diseases
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Mitochondrial dysfunction: A fatal blow in depression
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P2X7 Receptor Signaling in Stress and Depression
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The pharmacological properties of chrysophanol, the recent advances
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Augmented microglial endoplasmic reticulum-mitochondria contacts mediate depression-like behavior in mice induced by chronic social defeat stress
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Regulation of P2X7 receptor expression and function in the brain
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Pathological ATPergic Signaling in Major Depression and Bipolar Disorder
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Astrocytes and major depression: The purinergic avenue
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Purinergic Receptors of the Central Nervous System: Biology, PET Ligands, and Their Applications
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The role and mechanism of tryptophan – kynurenine metabolic pathway in depression
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Pathogenesis of depression and the potential for traditional Chinese medicine treatment
Ding, W., Wang, L., Li, L., Li, H., Wu, J., Zhang, J., & Wang, J. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1407869 · Cited by 66 · see citing works
P2X7 Variants in Oncogenesis
Pegoraro, A., Marchi, E. D., & Adinolfi, E. (2021) · Cells · doi:10.3390/cells10010189 · Cited by 63 · see citing works
Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease
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Structural basis for the functional properties of the P2X7 receptor for extracellular ATP
Jiang, L., Caseley, E. A., Muench, S. P., & Roger, S. (2021) · Purinergic Signalling · doi:10.1007/s11302-021-09790-x · Cited by 61 · see citing works
Dihydromyricetin Alleviates Diabetic Neuropathic Pain and Depression Comorbidity Symptoms by Inhibiting P2X7 Receptor
Guan, S., Shen, Y., Ge, H., Xiong, W., He, L., Liu, L., Yin, C., Wei, X., & Gao, Y. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00770 · Cited by 60 · see citing works
miR-124 ameliorates depressive-like behavior by targeting STAT3 to regulate microglial activation
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Plant-derived nanovesicles: Promising therapeutics and drug delivery nanoplatforms for brain disorders
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Microglia‐Derived Interleukin‐6 Triggers Astrocyte Apoptosis in the Hippocampus and Mediates Depression‐Like Behavior
Shen, S., Liang, L., Shi, T., Shen, Z., Yin, S., Zhang, J., Li, W., Mi, W., Wang, Y., Zhang, Y., et al. (2025) · Advanced Science · doi:10.1002/advs.202412556 · Cited by 53 · see citing works
The P2X7 receptor: a new therapeutic target in Alzheimer’s disease
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P2X7R antagonists in chronic stress-based depression models: a review
von Mücke-Heim, I.-A., Ries, C., Urbina-Treviño, L., & Deussing, J. M. (2021) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-021-01306-3 · Cited by 46 · see citing works
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The neuroinflammatory astrocytic P2X7 receptor: Alzheimer’s disease, ischemic brain injury, and epileptic state
Ahn, Y. H., Tang, Y., & Illés, P. (2023) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2023.2258281 · Cited by 41 · see citing works
High, in Contrast to Low Levels of Acute Stress Induce Depressive-like Behavior by Involving Astrocytic, in Addition to Microglial P2X7 Receptors in the Rodent Hippocampus
Zhao, Y.-F., Ren, W.-J., Zhang, Y., He, J., Yin, H., Liao, Y., Rubini, P., Deussing, J. M., Verkhratsky, A., Yuan, Z., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031904 · Cited by 40 · see citing works
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Novel Molecular Targets of Antidepressants
Jarończyk, M., & Walory, J. (2022) · Molecules · doi:10.3390/molecules27020533 · Cited by 40 · see citing works
Association of purinergic receptor P2RX7 gene polymorphisms with depression symptoms
Vereczkei, A., Abdul-Rahman, O., Halmai, Z., Nagy, G., Székely, A., Somogyi, A., Faludi, G., & Nemoda, Z. (2019) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2019.01.006 · Cited by 37 · see citing works
To Inhibit or Enhance? Is There a Benefit to Positive Allosteric Modulation of P2X Receptors?
Stokes, L., Bidula, S., Bibic, L., & Allum, E. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00627 · Cited by 34 · see citing works
FTY720 in CNS injuries: Molecular mechanisms and therapeutic potential
Zhang, L., & Wang, H. (2020) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2020.08.013 · Cited by 34 · see citing works
Role of neuroglia in neuropathic pain and depression
Liu, Q., Li, R., Yang, W., Cui, R., & Li, B. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105957 · Cited by 35 · see citing works
Acupuncture inhibits NLRP3 inflammasome activation in the prefrontal cortex of a chronic stress rat model of depression
Li, X., Wang, H., Li, C., Wu, J., Lü, J., Guo, J., & Tu, Y. (2021) · The Anatomical Record · doi:10.1002/ar.24778 · Cited by 31 · see citing works
Cross-ancestry genome-wide association study and systems-level integrative analyses implicate new risk genes and therapeutic targets for depression
Li, Y., Dang, X., Chen, R., Teng, Z., Wang, J., Li, S., Yue, Y., Mitchell, B. L., Zeng, Y., Yao, Y.-G., et al. (2025) · Nature Human Behaviour · doi:10.1038/s41562-024-02073-6 · Cited by 30 · see citing works
Animal Models for the Investigation of P2X7 Receptors
Sluyter, R., Adriouch, S., Fuller, S. J., Nicke, A., Sophocleous, R. A., & Watson, D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24098225 · Cited by 26 · see citing works
Design, Synthesis, and Biological Evaluation of Novel P2X7 Receptor Antagonists for the Treatment of Septic Acute Kidney Injury
Zhang, R., Su, K., Yang, L., Tang, M., Zhao, M., Ye, N., Cai, X., Jiang, X., Li, N., Peng, J., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00837 · Cited by 26 · see citing works
Beyond Seizure Control: Treating Comorbidities in Epilepsy via Targeting of the P2X7 Receptor
Gil, B., Smith, J., Tang, Y., Illés, P., & Engel, T. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23042380 · Cited by 26 · see citing works
Cuscutae semen alleviates CUS-induced depression-like behaviors in mice via the gut microbiota-neuroinflammation axis
Hou, L., Liu, Y., Zhu, C., Miao, J., Zhou, W., Tang, Y., Meng, H., & Liu, S. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1107781 · Cited by 26 · see citing works
P2X7 Variants in Pathophysiology
Pegoraro, A., Grignolo, M., Ruo, L., Ricci, L., & Adinolfi, E. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25126673 · Cited by 25 · see citing works
Effects of adjunctive inflammatory modulation on IL-1β in treatment resistant bipolar depression
Murata, S., Murphy, M. L. M., Hoppensteadt, D., Fareed, J., Welborn, A., & Halaris, A. E. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.01.004 · Cited by 24 · see citing works
Integrating UHPLC-MS/MS quantitative analysis and exogenous purine supplementation to elucidate the antidepressant mechanism of Chaigui granules by regulating purine metabolism
Chen, J., Li, T., Huang, D., Gong, W., Tian, J., Gao, X., Qin, X., Du, G., & Zhou, Y. (2023) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2023.08.008 · Cited by 24 · see citing works
P2X7 receptor-mediated depression-like reactions arising in the mouse medial prefrontal cortex
Ren, W., Zhao, Y.-F., Li, J., Rubini, P., Yuan, Z., Tang, Y., & Illés, P. (2023) · Cerebral Cortex · doi:10.1093/cercor/bhad166 · Cited by 24 · see citing works
Deviant reporter expression and P2X4 passenger gene overexpression in the soluble EGFP BAC transgenic P2X7 reporter mouse model
Ramírez-Fernández, A., Urbina-Treviño, L., Conte, G., Alves, M., Rissiek, B., Durner, A., Scalbert, N., Zhang, J., Magnus, T. U., Koch‐Nolte, F., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-76428-0 · Cited by 22 · see citing works
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P2X7 Receptor as a Potential Target for Major Depressive Disorder
Huang, Z., & Tan, S. (2021) · Current Drug Targets · doi:10.2174/1389450122666210120141908 · Cited by 20 · see citing works
P2X7 Receptor-Related Genetic Mouse Models – Tools for Translational Research in Psychiatry
Urbina-Treviño, L., von Mücke-Heim, I.-A., & Deussing, J. M. (2022) · Frontiers in Neural Circuits · doi:10.3389/fncir.2022.876304 · Cited by 22 · see citing works
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Increased Synaptic ATP Release and CD73-Mediated Formation of Extracellular Adenosine in the Control of Behavioral and Electrophysiological Modifications Caused by Chronic Stress
Dias, L., Pochmann, D., Lemos, C., Silva, H. B. L., Real, J. I., Gonçalves, F. Q., Rial, D., Gonçalves, N., Simões, A. P., Ferreira, S. G., et al. (2023) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.2c00810 · Cited by 21 · see citing works
A Possible Causal Involvement of Neuroinflammatory, Purinergic P2X7 Receptors in Psychiatric Disorders
Tang, Y., Illes, P., Zhang, Y., Yin, H.-Y., & Rubini, P. (2022) · Current Neuropharmacology · doi:10.2174/1570159x20666220302152400 · Cited by 20 · see citing works
The neurobiological mechanisms and therapeutic prospect of extracellular ATP in depression
Wang, K., Huang, S., Fu, D., Yang, X., Ma, L., Zhang, T., Zhao, W., Deng, D., Ding, Y., Zhang, Y., et al. (2024) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14536 · Cited by 19 · see citing works
Stress-Related Brain Neuroinflammation Impact in Depression: Role of the Corticotropin-Releasing Hormone System and P2X7 Receptor
Silberstein, S., Liberman, A. C., Claro, P. A. D. S., Ugo, M. B., Deussing, J. M., & ARZT, E. S. (2021) · NeuroImmunoModulation · doi:10.1159/000515130 · Cited by 19 · see citing works
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Neuroprotection of exercise: P2X4R and P2X7R regulate BDNF actions
Sun, B.-X., Peng, A., Liu, P., Wang, M., Ding, H., Hu, Y., & Kang, L. (2022) · Purinergic Signalling · doi:10.1007/s11302-022-09879-x · Cited by 19 · see citing works
The P2X7 receptor in mood disorders: Emerging target in immunopsychiatry, from bench to bedside
von Mücke-Heim, I.-A., & Deussing, J. M. (2022) · Neuropharmacology · doi:10.1016/j.neuropharm.2022.109366 · Cited by 18 · see citing works
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Potential applications of mesoporous silica nanoparticles for the treatment of neurological disorders
Bhatane, D., Pamshong, S. R., Sarnaik, S., Prabakaran, A., & Alexander, A. (2023) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2023.104970 · Cited by 17 · see citing works
P2X7 receptors from the perspective of NLRP3 inflammasome pathway in depression: Potential role of cannabidiol
Akçay, E., & Karataş, H. (2024) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2024.100853 · Cited by 18 · see citing works
Recent Advances in the Development of Antidepressants Targeting the Purinergic P2X7 Receptor
Lee, S., Ha, H., Jang, J., & Byun, Y. (2022) · Current Medicinal Chemistry · doi:10.2174/0929867329666220629141418 · Cited by 16 · see citing works
P2RX7 gene variation mediates the effect of childhood adversity and recent stress on the severity of depressive symptoms
Kristóf, Z., Eszlári, N., Sütöri, S., Gál, Z., Török, D., Baksa, D., Petschner, P., Sperlágh, B., Anderson, I. M., Deakin, J. F. W., et al. (2021) · PLoS ONE · doi:10.1371/journal.pone.0252766 · Cited by 16 · see citing works
Bipolar mania and epilepsy pathophysiology and treatment may converge in purine metabolism: A new perspective on available evidence
Daniels, S. D., & Boison, D. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109756 · Cited by 15 · see citing works
The human P2X7 receptor alters microglial morphology and cytokine secretion following immunomodulation
von Mücke-Heim, I.-A., Martin, J. N., Uhr, M., Ries, C., & Deussing, J. M. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1148190 · Cited by 13 · see citing works
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Sirtuin Type 1 Mediates the Antidepressant Effect of S-Ketamine in a Chronic Unpredictable Stress Model
Hou, L., Miao, J., Meng, H., Liu, X., Wang, D., Tan, Y., & Li, C. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.855810 · Cited by 11 · see citing works
P2X7 receptor: a potential target for treating comorbid anxiety and depression
Liu, J. H., Liu, T.-T., Mou, L., Zhang, Y., Chen, X., Wang, Q., Deng, B.-L., & Liu, J. (2024) · Purinergic Signalling · doi:10.1007/s11302-024-10007-0 · Cited by 10 · see citing works
Origin, distribution, and function of three frequent coding polymorphisms in the gene for the human P2X7 ion channel
Schäfer, W., Stähler, T., Pinto-Espinoza, C., Danquah, W., Knop, J., Rissiek, B., Haag, F., & Koch‐Nolte, F. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1033135 · Cited by 10 · see citing works
Antidepressant Drug Discovery and Development: Mechanism and Drug Design Based on Small Molecules
Yao, C., Jiang, X., Ye, X., Xie, T., & Bai, R. (2022) · Advanced Therapeutics · doi:10.1002/adtp.202200007 · Cited by 10 · see citing works
Purinergic modulation of major depressive disorder: Experimental findings, pathogenesis and therapeutic opportunities
Ren, X.-Y., Rubini, P., Engel, T., Tang, Y., & Illés, P. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107989 · Cited by 9 · see citing works
Schisandrin B Alleviates Diabetic Cardiac Autonomic neuropathy Induced by P2X7 Receptor in Superior Cervical Ganglion via NLRP3
Zhang, Z., Guo, H., Hu, Z., Zhou, C., Hu, Q., Peng, H. Y., Tang, G., Xiao, Z., Pi, L., & Li, G. (2023) · Disease Markers · doi:10.1155/2023/9956950 · Cited by 9 · see citing works
Mitochondrial metabolic reprogramming of microglia in neuroinflammation: Implications for major depressive disorder
Wang, Y., Chen, C.-Y., Yang, X., Lei, L., & Zhang, Y. (2025) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2025.111566 · Cited by 8 · see citing works
Tet1/DLL3/Notch1 signal pathway affects hippocampal neurogenesis and regulates depression-like behaviour in mice
Shuang, R., Gao, T., Sun, Z., Tong, Y. A., Zhao, K., & Wang, H. (2024) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2024.176417 · Cited by 8 · see citing works
Targeting calciumopathy for neuroprotection: focus on calcium channels Cav1, Orai1 and P2X7
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Authors: Deussing, J. M., & Arzt, E.
Affiliations: Max Planck Institute of Psychiatry (DE)
Max Planck Society (DE)
Corresponding author: Deussing, Jan M.
ORCID: Deussing, Jan M.
Arzt, Eduardo
Venue: Trends in Molecular Medicine
Publisher: Elsevier BV
Published: 2018-09
Volume: 24
Issue: 9
Pages: 736-747
ISSN: 1471-4914 (ISSN-L)
DOI: 10.1016/j.molmed.2018.07.005
OpenAlex: W2885132844
Cited by: 97
References: 98
Citations by year: 2026: 6 · 2025: 15 · 2024: 11 · 2023: 13 · 2022: 18 · 2021: 11 · 2020: 12 · 2019: 7 · 2018: 3
FWCI: 0.97
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Trends in Molecular Medicine (publishedVersion)
PubMed (publishedVersion)
MPG.PuRe (Max Planck Society) (submittedVersion)
Conicet (submittedVersion, cc-by-nc-nd)
Funders: Bundesministerium für Bildung und Forschung (FKZ 01ZX1314H)
Consejo Nacional de Investigaciones Científicas y Técnicas
Agencia Nacional de Promoción Científica y Tecnológica
Max-Planck-Gesellschaft
Universidad de Buenos Aires
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords: P2X7 receptor, depression, therapeutic target, inflammatory signaling, inflammatory cytokines, IL-1β, genetic risk factors, bipolar disorder, pharmacotherapy
MeSH terms: Animals, Depression, Depressive Disorder, Humans, Inflammation, Cytokines, Mutation, Missense, Polymorphism, Single Nucleotide, Drug Discovery, Receptors, Purinergic P2X7, Molecular Targeted Therapy

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P2X7 Receptor: A Potential Therapeutic Target for Depression?

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