Glutamate release and synapsin-I phosphorylation induced by P2X7 receptors activation in cerebellar granule neurons
Abstract
The present work reports that activation of P2X7 receptor induces synaptic vesicle release in granule neurons and phosphorylation of synapsin-I by calcium-calmodulin-dependent protein kinase II (CaMKII), which in turn modulates secretory event. ATP, in absence of magnesium, induced a concentration-dependent glutamate release with an EC50 value of 1.95 microM. The involvement of P2X7 receptor was suggested when maximal secretory response was significantly reduced by the selective P2X7 antagonist Brilliant Blue G (BBG; 100 nM) and abolished by removing extracellular Ca2+. The involvement of P2X7 receptor on synaptic vesicle release was confirmed by measuring the release of FM 1-43 dye. In this case, pharmacological activation of P2X7 was achieved with the more selective agonist 2'-3'-o-(4-benzoylbenzoyl)-adenosine 5'-triphosphate (BzATP; 100 microM) showing a significant FM 1-43 release that was blocked by BBG (100 nM), by Zn2+ ions (100 microM), both P2X7 blockers, but not by suramin (100 microM), antagonist of P2X1, P2X2, P2X3 and P2X5. In addition, BzATP, through P2X7 receptor activation, significantly increased the phosphorylation of synapsin-I, the main presynaptic target of CaMKII. Both effects mediated by BzATP were inhibited by the CaMKII inhibitors KN-62 (10 microM) and KN-93 (10 microM). These results suggest, therefore, that Ca2+ entrance mediated by P2X7 receptor induces glutamate release and in parallel synapsin-I phosphorylation.
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Studies in pure neuronal cell cultures and synaptosomes confirm that stimulation of P2X7R expressed in nerve terminals favors glutamate and GABA release.
“The effects mediated by P2X7R in glial cells and adenosine can be avoided in studies in pure neuronal cell cultures [106] and synaptosomes [107,108,109], which confirms that stimulation of P2X7R expressed in nerve terminals favors glutamate and GABA release.”
From P2X7 Receptor Signaling in Stress and Depression (2019) · cites this paper as [106]
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“P2X7R is well documented to modulate glutamatergic activity, where P2X7R facilitates glutamate release from astrocytes and neurons into the extracellular space, leading to excitotoxicity (Deuchars et al., 2001; Leon et al., 2008; Sperlagh et al., 2006).”
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BackgroundP2X7 receptors in the central nervous system
Miras‐Portugal, M. T., Ortega, F., Gómez‐Villafuertes, R., Gualix, J., Pérez‐Sen, R., & Delicado, E. G. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114472 · Cited by 24 · see citing works
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“Cerebellar granule neurons were loaded with FM 1-43 following the protocol described by Mozhayeva et al. (2002) and adapted by León et al. (2008).”
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“We previously reported that activation of either P2X3 or P2X7 receptors induces an increase in cytosolic Ca2+ in cerebellar granule neurons, resulting in the exocytotic release of glutamate and the subsequent enhancement of synapsin-1 phosphorylation (Leon et al., 2006, 2008).”
BackgroundSelf-citationHabbas, S., Ango, F., Daniel, H., & Galante, M. (2011) · Glia · doi:10.1002/glia.21224 · Cited by 17 · see citing works
Gao, Z., van Woerden, G. M., Elgersma, Y., Zeeuw, C. I. D., & Hoebeek, F. E. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00016 · Cited by 16 · see citing works
Sánchez‐Nogueiro, J., Marín‐García, P., Bustillo, D., Olivos-Oré, L. A., Miras‐Portugal, M. T., & Artalejo, A. R. (2014) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2014.10.036 · Cited by 15 · see citing works
Self-citationSuppression of GABA input by A1 adenosine receptor activation in rat cerebellar granule cells
Courjaret, R. J., Tröger, M., & Deitmer, J. W. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.05.045 · Cited by 15 · see citing works
Sebastián‐Serrano, Á., de Diego-García, L., Lauro, C. D., Bianchi, C., & Dı́az-Hernández, M. (2019) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2019.01.031 · Cited by 13 · see citing works
Fluorescent dyes as a reliable tool in P2X7 receptor-associated pore studies
Ferreira, L., Pereira, L. D. O. R., & Faria, R. X. (2015) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-015-9613-0 · Cited by 10 · see citing works
“2009; Sadananda et al. 2009; Yip et al. 2009; Lohman et al. 2012) and glutamate (Liu et al. 2006, León et al. 2008, Musella et al. 2009; Sun et al. 2009; Orellana et al. 2014).”
Jackson, T., Seifi, M., Górecki, D. C., & Swinny, J. D. (2021) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-021-01110-6 · Cited by 10 · see citing works
P2X7R modulation of visually evoked synaptic responses in the retina
Chavda, S., Luthert, P. J., & Salt, T. E. (2016) · Purinergic Signalling · doi:10.1007/s11302-016-9522-7 · Cited by 10 · see citing works
“P2X7R-mediated neurotransmitter release has been detected in the cerebellum [18], cerebral cortex and midbrain preparations [19–21], hippocampus [22] and neuromuscular junction [23].”
BackgroundThe P2X7 receptor in depression: Novel insights and therapeutic implications
Zhong, Y.-T., Pi, C., Zuo, Y., Yan, W., Li, W., Jiang, Y., Lei, T., Zheng, W., Jiang, J., Yang, Y., et al. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.107011 · Cited by 9 · see citing works
Purinergic Modulation of Granule Cells
Courjaret, R. J., Miras‐Portugal, M. T., & Deitmer, J. W. (2010) · The Cerebellum · doi:10.1007/s12311-010-0196-3 · Cited by 9 · see citing works
“Upon stimulation, they are able to induce exocytotic glutamate release, and, at the same time, via CaMKII activation, induce synapsin phosphorylation [33, 59 ].”
BackgroundSelf-citationP2X7 receptors and pannexin1 hemichannels shape presynaptic transmission
Vitureira, N., Rafael, A., & Abudara, V. (2023) · Purinergic Signalling · doi:10.1007/s11302-023-09965-8 · Cited by 7 · see citing works
Purinergic Signalling in the Central Nervous System
Burnstock, G., & Verkhratsky, A. (2012) · Springer eBooks · doi:10.1007/978-3-642-28863-0_8 · Cited by 6 · see citing works
Chang, A., Hung, C., Hsieh, P., Ko, H.-J., & Wang, S. (2021) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2021.046 · Cited by 5 · see citing works
“Contribution of decreased CaMKII/synapsin I pathway to the eupafolin-mediated inhibition of glutamate release The involvement of CaMKII in the eupafolin-mediated inhibition of glutamate release was studied using the selective CaMKII inhibitor KN62 (10 μM) (León et al., 2008).”
BackgroundMethodContribution of microglia to the epileptiform activity that results from neonatal hypoxia
Leavy, A., Phelan, J., & Jimenez-Mateos, E. M. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.109968 · Cited by 4 · see citing works
“…of P2X7 triggers an intracellular cascade, resulting in the release of the proinflammatory cytokine IL-1 β , which, as discussed earlier, increases glutamatergic neurotransmission (Rossi et al., 2012; Vezzani and Baram, 2007; Deuchars et al., 2001; Leon et al., 2008; Sperlagh et al., 2006).”
BackgroundGil‐Redondo, J. C., Queipo, M. J., Trueba, Y., Llorente-Sáez, C., Serrano-López, J., Ortega, F., Gómez‐Villafuertes, R., Pérez‐Sen, R., & Delicado, E. G. (2023) · Purinergic Signalling · doi:10.1007/s11302-023-09970-x · Cited by 4 · see citing works
“P2X7R has been shown to be present in rat cerebellar cells [18, 19] and while prolonged P2X7R stimulation does not affect the survival of cerebellar astrocytes or granule neurons [20, 21], its activation does prevent the cerebellar granule neuron toxicity induced by high concentrations of glutamate…”
BackgroundFaria, R. X., Ferreira, L. G. B., & Alves, L. A. (2012) · InTech eBooks · doi:10.5772/29146 · Cited by 2 · see citing works
“In addition, they are all permeable to the anionic ATP4molecule (Nagasawa et al, 2009; Pellegatti et al, 2005; Yip et al, 2009) and glutamate (Léon et al, 2008).”
BackgroundReceptores de nucleótidos y su implicación en los mecanismos del dolor y analgesia
Miras‐Portugal, M. T. (2015)
Self-citationCross-talk between glutamate and nucleotide receptors in cerebellar granule neurons in culture
Salas, E., León, D., Sánchez‐Nogueiro, J., Marín‐García, P., & Miras‐Portugal, M. T. (2010) · Anales de la Real Academia Nacional de Farmacia
Self-citationAn S-Palmitoyltransferase Modulates P2X7 Function
Levenstein, D. (2015) · eCommons (Cornell University)
do Carmo, M. R. S. (2015) · LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas)
Purinergic Signaling in Depression
Ribeiro, D. E., Kaster, M. P., Ulrich, H., Lisboa, S. F. D. S., & Joca, S. R. L. (2023) · Springer eBooks · doi:10.1007/978-3-031-26945-5_7
Chen, D., Zhang, S., Guo, Y., Zhao, X., Mao, P., Hai, X., Yang, Z., & 赵光海 (2026) · Current Pain and Headache Reports · doi:10.1007/s11916-026-01511-6
BindingDB (2014) · UC San Diego · doi:10.7270/q2jq12dd
- Authors
- León, D., Sánchez-Nogueiro, J., Marín-García, P., & Miras-Portugal, M. T.
- Affiliations
- Universidad Complutense de Madrid (ES)
- ORCID
- León, David
- Venue
- Neurochemistry International
- Publisher
- Elsevier BV
- Published
- 2008-05
- Volume
- 52
- Issue
- 6
- Pages
- 1148-1159
- ISSN
- 0197-0186 (ISSN-L)
- OpenAlex
- W2025990788
- Cited by
- 53
- References
- 50
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 4 · 2022: 1 · 2021: 5 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 3 · 2016: 3 · 2015: 8 · 2014: 3 · 2013: 3 · 2012: 4
- FWCI
- 2.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurochemistry International (publishedVersion)
- PubMed (publishedVersion)
- Funders
- “la Caixa” Foundation (BM05-114-0)
- Ministerio de Educación, Cultura y Deporte (BFU2005-02079)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- P2X7 receptor, glutamate release, synapsin I phosphorylation, CaMKII, cerebellar granule cells, synaptic vesicle release, ATP, BzATP, Brilliant Blue G, calcium influx, presynaptic modulation, zinc
- MeSH terms
- Adenosine Triphosphate, Quaternary Ammonium Compounds, Animals, Animals, Newborn, Benzenesulfonates, Cells, Cultured, Cerebellar Cortex, Dose-Response Relationship, Drug, Enzyme Inhibitors, Synaptic Transmission, Neurons, Phosphorylation, Pyridinium Compounds, Suramin, Synaptic Vesicles, Synapsins, Rats, Wistar, Presynaptic Terminals, Receptors, Purinergic P2, Glutamic Acid, Rats, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Receptors, Purinergic P2X7, Purinergic P2 Receptor Agonists, Purinergic P2 Receptor Antagonists
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