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Grant support

We are grateful to Dr. Mark Sefton for his revision of the manuscript. This work was funded by the Spanish Ministerio de Economia y Competitividad (MINECO, BFU 2014-53654-P) and the "Red de Excelencia Consolider-Ingenio Spanish Ion Channel Initiative'' (BFU2015-70067REDC); by the Comunidad de Madrid (BRADE-CMS2013/ICE-2958), and by a Fundacion Ramon Areces Grant (PR2018/16-02). FO acknowledges the Ramon y Cajal Program from the Spanish Ministerio de Economia y Competitividad (MEC: RYC-2013-13290).

Analysis of institutional authors

Gil-Redondo, Juan CAuthorPerez-Sen, RaquelCorresponding Author

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Article

P2X7 Nucleotide and EGF Receptors Exert Dual Modulation of the Dual-Specificity Phosphatase 6 (MKP-3) in Granule Neurons and Astrocytes, Contributing to Negative Feedback on ERK Signaling

Publicated to:Frontiers in Molecular Neuroscience. 10 448- - 2018-01-10 10(), DOI: 10.3389/fnmol.2017.00448

Authors: Jose Queipo, Ma; Gil-Redondo, Juan C.; Morente, Veronica; Ortega, Felipe; Teresa Miras-Portugal, Ma; Delicado, Esmerilda G.; Perez-Sen, Raquel;

Affiliations

Abstract

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) play a central role in the intracellular signaling of P2X7 nucleotide receptors in neurons and glial cells. Fine spatio-temporal tuning of mitogen-activated protein (MAP) kinases is essential to regulate their biological activity. MAP kinase phosphatases (MKPs) are dual specificity protein phosphatases (DUSPs) that dephosphorylate phosphothreonine and phosphotyrosine residues in MAP kinases. This study focuses on how DUSP, DUSP6/MKP3, a phosphatase specific for ERK1/2 is regulated by the P2X7 nucleotide receptor in cerebellar granule neurons and astrocytes. Stimulation with the specific P2X7 agonist, BzATP, or epidermal growth factor (EGF) (positive control for ERK activation) regulates the levels of DUSP6 in a time dependent manner. Both agonists promote a decline in DUSP6 protein, reaching minimal levels after 30 min yet recovering to basal levels after 1 h. The initial loss of protein occurs through proteasomal degradation, as confirmed in experiments with the proteasome inhibitor, MG-132. Studies carried out with Actinomycin D demonstrated that the enhanced transcription of the Dusp6 gene is responsible for recovering the DUSP6 protein levels. Interestingly, ERK1/2 proteins are involved in the biphasic regulation of the protein phosphatase, being required for both the degradation and the recovery phase. We show that direct Ser197 phosphorylation of DUSP6 by ERK1/2 proteins could be part of the mechanism regulating their cytosolic levels, at least in glial cells. Thus, the ERK1/2 activated by P2X7 receptors exerts positive feedback on these kinase's own activity, promoting the degradation of one of their major inactivators in the cytosolic compartment, DUSP6, both in granule neurons and astrocytes. This feedback loop seems to function as a common universal mechanism to regulate ERK signaling in neural and non-neural cells.

Keywords

astrocytesdusp6erksglial cellsmkp3p2x7 receptorsActivated protein-kinaseAstrocytesCell-deathCerebellar astrocytesCross-talkDown-regulationDusp6Dusp6/mkp-3ErksGlial cellsGranule neuronsMechanical allodyniaMkp3P2x7 receptorsProteasomal degradationRegulated kinase

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Frontiers in Molecular Neuroscience due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2018, it was in position 87/266, thus managing to position itself as a Q2 (Segundo Cuartil), in the category Neurosciences. Notably, the journal is positioned en el Cuartil Q2 para la agencia Scopus (SJR) en la categoría Molecular Biology.

From a relative perspective, and based on the normalized impact indicator calculated from the Field Citation Ratio (FCR) of the Dimensions source, it yields a value of: 2.28, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: Dimensions Jun 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-06-02, the following number of citations:

  • WoS: 20
  • Scopus: 21
  • OpenCitations: 22

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-06-02:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 15.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 15 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 2.6.
  • The number of mentions on the social network X (formerly Twitter): 6 (Altmetric).

Leadership analysis of institutional authors

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: Last Author (PEREZ ARNAIZ, PATRICIA).

the author responsible for correspondence tasks has been PEREZ ARNAIZ, PATRICIA.