DUSP1/MKP-1 represents another piece in the P2X7R intracellular signaling puzzle in cerebellar cells: our last journey with Mª Teresa along the purinergic pathways of Eden.

IF 3 4区 医学 Q2 NEUROSCIENCES Purinergic Signalling Pub Date : 2024-04-01 Epub Date: 2023-09-30 DOI:10.1007/s11302-023-09970-x
Juan Carlos Gil-Redondo, María José Queipo, Yaiza Trueba, Celia Llorente-Sáez, Julia Serrano, Felipe Ortega, Rosa Gómez-Villafuertes, Raquel Pérez-Sen, Esmerilda G Delicado
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Abstract

The P2X7 receptor (P2X7R) stands out within the purinergic family as it has exclusive pharmacological and regulatory features, and it fulfills distinct roles depending on the type of stimulation and cellular environment. Tonic activation of P2X7R promotes cell proliferation, whereas sustained activation is associated with cell death. Yet strikingly, prolonged P2X7R activation in rat cerebellar granule neurons and astrocytes does not affect cell survival. The intracellular pathways activated by P2X7Rs involve proteins like MAPKs, ERK1/2 and p38, and interactions with growth factor receptors could explain their behavior in populations of rat cerebellar cells. In this study, we set out to characterize the intracellular mechanisms through which P2X7Rs and Trk receptors, EGFR (epidermal growth factor receptor) and BDNFR (brain-derived neurotrophic factor receptor), regulate the dual-specificity phosphatase DUSP1. In cerebellar astrocytes, the regulation of DUSP1 expression by P2X7R depends on ERK and p38 activation. EGFR stimulation can also induce DUSP1 expression, albeit less strongly than P2X7R. Conversely, EGF was virtually ineffective in regulating DUSP1 in granule neurons, a cell type in which BDNF is the main regulator of DUSP1 expression and P2X7R only induces a mild response. Indeed, the regulation of DUSP1 elicited by BDNF reflects the balance between both transcriptional and post-transcriptional mechanisms. Importantly, when the regulation of DUSP1 expression is compromised, the viability of both astrocytes and neurons is impaired, suggesting this phosphatase is essential to maintain proper cell cytoarchitecture and functioning.

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DUSP1/MKP-1代表了小脑细胞P2X7R细胞内信号传导难题中的另一块:我们与MªTeresa沿着伊甸园嘌呤能通路的最后一次旅程。
P2X7受体(P2X7R)在嘌呤能家族中脱颖而出,因为它具有独特的药理学和调节特征,并且根据刺激类型和细胞环境发挥不同的作用。P2X7R的强化激活促进细胞增殖,而持续激活与细胞死亡有关。然而,令人惊讶的是,大鼠小脑颗粒神经元和星形胶质细胞中P2X7R的长期激活并不影响细胞存活。P2X7Rs激活的细胞内通路涉及MAPKs、ERK1/2和p38等蛋白质,与生长因子受体的相互作用可以解释它们在大鼠小脑细胞群中的行为。在本研究中,我们着手表征P2X7Rs和Trk受体EGFR(表皮生长因子受体)和BDNFR(脑源性神经营养因子受体)调节双特异性磷酸酶DUSP1的细胞内机制。在小脑星形胶质细胞中,P2X7R对DUSP1表达的调节依赖于ERK和p38的激活。EGFR刺激也可以诱导DUSP1表达,尽管不如P2X7R强烈。相反,EGF在调节颗粒神经元中的DUSP1方面几乎无效,在颗粒神经元中,BDNF是DUSP1表达的主要调节因子,P2X7R仅诱导轻度反应。事实上,BDNF引发的DUSP1的调节反映了转录和转录后机制之间的平衡。重要的是,当DUSP1表达的调节受损时,星形胶质细胞和神经元的生存能力都会受损,这表明这种磷酸酶对维持适当的细胞结构和功能至关重要。
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来源期刊
Purinergic Signalling
Purinergic Signalling 医学-神经科学
CiteScore
6.60
自引率
17.10%
发文量
75
审稿时长
6-12 weeks
期刊介绍: Nucleotides and nucleosides are primitive biological molecules that were utilized early in evolution both as intracellular energy sources and as extracellular signalling molecules. ATP was first identified as a neurotransmitter and later as a co-transmitter with all the established neurotransmitters in both peripheral and central nervous systems. Four subtypes of P1 (adenosine) receptors, 7 subtypes of P2X ion channel receptors and 8 subtypes of P2Y G protein-coupled receptors have currently been identified. Since P2 receptors were first cloned in the early 1990’s, there is clear evidence for the widespread distribution of both P1 and P2 receptor subtypes in neuronal and non-neuronal cells, including glial, immune, bone, muscle, endothelial, epithelial and endocrine cells.
期刊最新文献
Correction to: Preparation and preliminary evaluation of a tritium-labeled allosteric P2X4 receptor antagonist. Machine learning-aided search for ligands of P2Y6 and other P2Y receptors. Purinergic regulation of pulmonary vascular tone. Role of ecto-5'-nucleotidase in bladder function activity and smooth muscle contractility. Unexpected role of microglia and P2Y12 in the induction of and emergence from anesthesia.
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