Abstract
The neuron-specific tyrosine phosphatase striatal-enriched phosphatase (STEP) is emerging as a key regulator of excitotoxicity, which is involved in the pathogenesis of both acute and chronic neurological diseases. However, the intracellular mechanisms that are regulated by STEP to confer neuroprotection against excitotoxic insults are not well understood. The present study investigates the role of STEP in regulating neuronal release of the proinflammatory prostanoid prostaglandin E2 (PGE2), which is associated with a wide range of pathological conditions. The findings show that glutamate-mediated activation of the N-methyl-D-aspartic acid receptor in STEP-deficient neurons leads to rapid and sustained increase in the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), a signaling molecule involved in the production of inflammatory mediators. Such sustained p38 MAPK activation increases the activity of cytosolic phospholipase A2, which catalyzes the release of arachidonic acid, the initial substrate for PGE2 biosynthesis. Sustained p38 MAPK activation also induces nuclear factor-κB–mediated increase in expression of cyclooxygenase-2 that is involved in the conversion of arachidonic acid to prostanoids, resulting in enhanced biosynthesis and release of PGE2 from neurons. Restoration of STEP function with a STEP mimetic (TAT-STEP-myc peptide) significantly decreases the activation of p38 MAPK–mediated cytosolic phospholipase A2/cyclooxygenase-2/PGE2 signaling cascade. This study identifies an important mechanism involved in the neuronal release of the proinflammatory mediator PGE2 after excitotoxic insult and highlights for the first time the immunomodulatory ability of a neuronal tyrosine phosphatase.
Highlights
Disorders [1, 2]
Excessive stimulation of neuronal N-methyl-Daspartic acid (NMDA) receptors (NMDARs) during an excitotoxic insult leads to intracellular Ca2+ overload and activation of a deleterious cascade of events resulting in neurotoxicity that eventually leads to brain damage
Our findings show that an excitatory insult in the absence of striatal-enriched phosphatase (STEP) triggers an inflammatory response through increased neuronal release of the proinflammatory prostanoid, prostaglandin E2 (PGE2), which involves p38 p38 mitogen-activated protein kinase (MAPK)–mediated increased cytosolic phospholipase A2 activation and nuclear factor-κB (NF-κB)-dependent cyclooxygenase-2 (COX-2) expression
Summary
Disorders [1, 2]. These include acute neurological conditions such as ischemic stroke and traumatic brain injury as well as chronic neurodegenerative diseases such as Huntington’s disease and amyotrophic lateral sclerosis [1]. Several studies have shown that p38 MAPK plays a role in glutamate-mediated neuronal excitotoxicity [12,13,14] Another potentially important finding is that the brain-enriched and neuron-specific tyrosine phosphatase striatal-enriched phosphatase (STEP) is a key regulator of p38 MAPK phosphorylation and activation in neurons [13]. STEP61 is the membrane-bound isoform of the STEP family that is ubiquitously expressed in the brain and is the predominant isoform expressed in primary cultured neurons [16,17,18] It is a signaling molecule downstream of NMDAR stimulation, whose activation after an excitotoxic insult provides initial neuroprotection by dephosphorylating and downregulating p38 MAPK activity, whereas degradation of active STEP over time leads to secondary activation of p38 MAPK, resulting in the progression of neuronal injury and brain damage [11, 13]. The findings present the novel concept that the tyrosine phosphatase STEP promotes neuroprotection against excitotoxic insult through regulation of neuroinflammatory responses
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
