Dual-Specificity Phosphatase Regulation in Neurons and Glial Cells

Abstract

Dual-specificity protein phosphatases comprise a protein phosphatase subfamily with selectivity towards mitogen-activated protein (MAP) kinases, also named MKPs, or mitogen-activated protein kinase (MAPK) phosphatases. As powerful regulators of the intensity and duration of MAPK signaling, a relevant role is envisioned for dual-specificity protein phosphatases (DUSPs) in the regulation of biological processes in the nervous system, such as differentiation, synaptic plasticity, and survival. Important neural mediators include nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) that contribute to DUSP transcriptional induction and post-translational mechanisms of DUSP protein stabilization to maintain neuronal survival and differentiation. Potent DUSP gene inducers also include cannabinoids, which preserve DUSP activity in inflammatory conditions. Additionally, nucleotides activating P2X7 and P2Y₁₃ nucleotide receptors behave as novel players in the regulation of DUSP function. They increase cell survival in stressful conditions, regulating DUSP protein turnover and inducing DUSP gene expression. In general terms, in the context of neural cells exposed to damaging conditions, the recovery of DUSP activity is neuroprotective and counteracts pro-apoptotic over-activation of p38 and JNK. In addition, remarkable changes in DUSP function take place during the onset of neuropathologies. The restoration of proper DUSP levels and recovery of MAPK homeostasis underlie the therapeutic effect, indicating that DUSPs can be relevant targets for brain diseases.

Keywords: BDNF; MAP kinases; P2X7; P2Y13; astrocytes; cannabinoids, granule neurons; dual-specificity phosphatases; nucleotide receptors.

Figure 1

Regulation of dual-specificity protein phosphatases (DUSP) protein levels and activity. DUSPs can be regulated at different levels by their own substrates, mitogen-activated protein (MAP) kinases at (1) transcriptional, (2) post-transcriptional, and (3) post-translational levels by several mechanisms. The latter involve (4,5) phosphorylation, (6) acetylation, (7) cysteine oxidation, and (8) caspase–mediated cleavage. These modifications can positively or negatively affect DUSP activities, as well as act as a shuttle to subcellular compartmentalization.

Figure 2

Scheme representing the neuroprotective role of some neurotrophins and nucleotide receptors through the regulation of MAPK and DUSP activity in neural cells. Tyrosine kinase receptors (BDNF, EGF, NGF and FGF), NMDA, and nucleotide ionotropic P2X7 and metabotropic P2Y₁₃ receptors regulate DUSP1, DUSP2, and DUSP6 levels through different mechanisms, involving transcriptional induction, turnover regulation, and protein stabilization. The reestablishment of DUSP activity is essential to avoid the over-activation of MAP kinases and cell death induced by different apoptotic insults in neurons and glial cells. Arrows indicate activation of MAPKs, DUSP expression and cell survival/death. T-bars indicate inhibition of MAPK activation and DUSP expression and activity.

Figure 3

Role of cannabinoid receptors in pain relief and inflammation. CB1 and CB2 receptors increase DUSP1 and DUSP6 expression in neurons and microglial cells, which contributes to counteracting the over-activation of ERK and p38 in different pain models. In microglial cells, DUSP1 expression induction takes place by a novel mechanism involving histone remodeling, which is independent of MAPK activation. DUSP activity prevents the microglia activation and the release of pro-inflammatory mediators.

Figure 4

The yin and yang of DUSP activity in brain diseases. This figure summarizes the current available data about DUSP activity in brain diseases, but they only represent the tip of the iceberg. Whereas the increase in DUSP expression can be beneficial for neurodegenerative diseases, it is detrimental for neurological disorders. The restoring of the appropriate levels of DUSP activity will be determined by the injury type and the spatiotemporal context.