Abstract
The neural precursor cell expressed by developmentally downregulated gene 4-2 (NEDD4-2) is a ubiquitin E3 ligase that has a high affinity toward binding and ubiquitinating glutamate ionotropic receptor α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type subunit 1 (GRIA1, also referred to GluR1 or GluA1). Since dysregulation of GRIA1 surface expression is relevant to the responsiveness to AMPA receptor (AMPAR) antagonists (perampanel and GYKI 52466) in chronic epilepsy rats, it is likely that NEDD4-2 may be involved in the pathogenesis of intractable epilepsy. However, the role of NEDD4-2-mediated GRIA1 ubiquitination in refractory seizures to AMPAR antagonists is still unknown. In the present study, both AMPAR antagonists recovered the impaired GRIA1 ubiquitination by regulating protein phosphatase 2B (PP2B)-extracellular signal-regulated kinase 1/2 (ERK1/2)-serum and glucocorticoid-regulated kinase 1 (SGK1)-NEDD4-2 signaling pathway in responders (whose seizure activities are responsive to AMPAR), but not non-responders (whose seizure activities were uncontrolled by AMPAR antagonists). In addition, cyclosporin A (CsA, a PP2B inhibitor) co-treatment improved the effects of AMPAR antagonists in non-responders, independent of AKT signaling pathway. Therefore, our findings suggest that dysregulation of PP2B-ERK1/2-SGK1-NEDD4-2-mediated GRIA1 ubiquitination may be responsible for refractory seizures and that this pathway may be a potential therapeutic target for improving the treatment of intractable epilepsy in response to AMPAR antagonists.
Highlights
We investigated the effects of AMPA receptor (AMPAR) antagonists on NEDD4-2mediated GRIA1 regulation in responders and non-responders of a LiCl-pilocarpine epilepsy rat model to elucidate the role of NEDD4-2 in Mesial temporal lobe epilepsy (MTLE)
In non-responders to perampanel and GYKI 52466, serum and glucocorticoid-regulated kinase 1 (SGK1) protein level, its S78 and S422 phosphorylation levels/ratios, and SGK1 ubiquitination were unaffected by each compound (Figure 4A–G and Figure S2). These findings indicate that AMPAR antagonists may selectively enhance SGK1 78 phosphorylation, which phosphorylates NEDD4-2 S448 site
NEDD4-2andi mice are very sensitive to 2,3dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline (NBQX, an AMPAR antagonist) with regard to spontaneous spike frequency, average spontaneous spike amplitude and electrode burst activity do not differ after amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or NBQX treatment for either genotype [11]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Epilepsy is a brain function disorder characterized by recurrent and unprovoked seizures. The prevalence of epilepsy in the general population is approximately 0.6−0.8% [1]. Initial/acute prolonged seizure (status epilepticus, SE), trauma, stroke or infections are postulated as precipitating factors of epilepsy [2]. Mesial temporal lobe epilepsy (MTLE) is the most common form of epilepsy and a medically intractable syndrome that is partially or totally uncontrolled by conventional anti-epileptic drug (AED) treatments [3]. Disturbances in glutamatergic/GABAergic transmissions and the related signaling pathways are associated with the pathogenesis of MTLE in humans, the underlying mechanisms of MTLE remain largely unclear
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