PDI regulates seizure activity via NMDA receptor redox in rats

Kim, Ji Yang; Ko, Ah-Rhem; Hyun, Hye-Won; Min, Su-Ji; Kim, Jieun

doi:10.1038/srep42491

Cited by 17 publications

(55 citation statements)

References 57 publications

(105 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the ratio of total-and SNO-thiol levels on PSD95 was significantly increased in epileptic rats (p < 0.05 vs. control animals, n = 7; Figure 4A,B). Consistent with our previous studies [5], NR2A expression in epilepsy animals was lower than that in control animals. In contrast, the total-and SNO-thiol levels on NR2A were significantly increased in epileptic rats (p < 0.05 vs. control animals, Student's t-test, n = 7; Figure 4A,C).…”

Section: S-nitrosylation and Disulfide Bond Formation On Psd95 In Episupporting

confidence: 93%

“…However, PILO increased the number of SNO-thiols, but not total thiols, on PSD95 (p < 0.05 vs. saline, Student's t-test, n = 7; Figure 2A,B). Consistent with our previous study [5], PILO reduced NR2A expression (p < 0.05 vs. saline, Student's t-test, n = 7; Figure 2A,C), but elevated the total-and SNO-thiol levels on NR2A (p < 0.05, Student's t-test, n = 7; Figure 2A,C). PILO inhibited the NR2A-PSD95 binding (p < 0.05 vs. saline, Student's t-test, n = 7; Figure 2D,E).…”

Section: Introductionsupporting

confidence: 91%

“…PILO decreased the colocalization of NR2A within PSD95 puncta, but increased colocalization of NR2A within PDI puncta (p < 0.05 vs. saline, Student's t-test, n = 7, respectively; Figure 3C). Since PDI is a redox-active enzyme for NR2A [5], these findings indicate that PDI may participate in the reduction of disulfide bonds on NR2A, but not on PSD95, following acute seizures. In addition, increased NO concentration may nitrosylate free thiols on PSD95 and NR2A.…”

Section: Introductionmentioning

confidence: 82%

“…The N-methyl-D-aspartate receptor (NMDAR) is one of the major excitatory receptors contributing to neurotransmission, synaptic plasticity and neuronal damage [1][2][3]. In addition, the NMDAR plays a key role in seizure generation and epileptogenesis [4][5][6]. NMDAR activity is regulated by redox modulation of disulfide bonds (S-S) and S-nitrosylation (-SNO) of cysteine residues on NR1 and NR2A subunits: Oxidation of free thiol (-SH) to disulfide bond and S-nitrosylation both inhibit NMDAR-evoked currents [7,8].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we have reported that protein disulfide isomerase (PDI), a member of the thioredoxin superfamily of redox proteins, increases seizure susceptibility via sulfhydration (reduction) of disulfide bonds (S-S to -SH + -SH) on NMDAR. Briefly, PDI knockdown or its neutralization prevents the induction of status epilepticus (SE, prolonged seizure activity) in response to pilocarpine (PILO) and inhibits spontaneous seizure activity in epileptic rats [5,9]. Therefore, the regulation of PDI activity is one of the potential therapeutic targets for epilepsy via NMDAR redox.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

PDI-Mediated Reduction of Disulfide Bond on PSD95 Increases Spontaneous Seizure Activity by Regulating NR2A–PSD95 Interaction in Epileptic Rats Independent of S-Nitrosylation

Lee

Kim

2020

IJMS

Self Cite

View full text Add to dashboard Cite

Postsynaptic density-95 (PSD95), a major scaffolding protein, is critical in coupling N-methyl-D-aspartate receptor (NMDAR) to cellular signaling networks in the central nervous system. A couple of cysteine residues in the N-terminus of PSD95 are potential sites for disulfide bonding, S-nitrosylation and/or palmitoylation. Protein disulfide isomerase (PDI) reduces disulfide bonds (S-S) to free thiol (-SH) on various proteins. However, the involvement of PDI in disulfide bond formation/S-nitrosylation of PSD95 and its role in epilepsy are still unknown. In the present study, acute seizure activity significantly increased the bindings of PDI to NR2A, but not to PSD95, while it decreased the NR2A-PSD95 binding. In addition, pilocarpine-induced seizures increased the amount of nitrosylated (SNO-) thiols, not total (free and SNO-) thiols, on PSD95. Unlike acute seizure, spontaneous seizing rats showed the increases in PDI-PSD95 binding, total-and SNO-thiol levels on PSD95, and NR2A-PSD95 interaction. PDI siRNA effectively reduced spontaneous seizure activity with decreases in total thiol level on PSD95 and NR2A-PSD95 association. These findings indicate that PDI-mediated reduction of disulfide-bond formations may facilitate the NR2A-PSD95 binding and contribute to spontaneous seizure generation in epileptic animals. N-terminal of the first two PDZ domains of the PSD95 recognizes a four amino acid consensus sequence (-E-S/T-D-V) and allows it to bivalently link various ion channels, including NR2 subunits [11][12][13]. PSD95 is also required for NMDAR-mediated neuronal nitric oxide synthase (nNOS) activation [14]. Indeed, suppression of PSD95 expression inhibits NMDAR-mediated NOS activation and neuronal excitotoxicity [14]. However, synaptic NMDAR currents, subunit expression, localization and synaptic morphology remain unaltered in transgenic mice lacking PSD95, but they also shift the frequency dependence of NMDAR-mediated synaptic plasticity and impair spatial learning [15]. Thus, it is emphasized that PSD95 is critical in coupling NMDAR to cellular signaling networks and plays an important role in their biological functions within the central nervous system.On the other hand, the N-terminus of PSD95 contains a pair of cysteine residue (cysteine 3 and 5 sites). These cysteine residues are potential sites for disulfide-bond formation, S-nitrosylation and/or palmitoylation [16,17]. In addition, disulfide linkage of each PSD95 protein in these sites mediates its multimerization as supramolecular aggregates [18] and facilitates receptor-clustering activity [19]. S-nitrosylation of these sites also influences PSD95 palmitoylation and its clustering at synapses [20]. Given the reductive role of PDI in disulfide bonds, it is interesting to evaluate whether PDI mediates disulfide-bond formation or S-nitrosylation on PSD95 during seizure generation. Here, we demonstrate that PILO-induced acute seizure activity significantly increased the bindings of PDI to NR2A, but not to PSD95, while it decreased the NR2A-PSD95. In additi...

show abstract

Section: S-nitrosylation and Disulfide Bond Formation On Psd95 In Episupporting

confidence: 93%

Section: Introductionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 82%