Redox modulation and S-nitrosylation of
cysteine residues are the post-translational modifications of
N-methyl-D-aspartate receptor (NMDAR) to regulate its functionality. Recently, we have reported that
protein disulfide isomerase (PDI) reduces
disulfide bond (S-S) to free
thiol (-SH) on NMDAR. Since PDI is a modulator of S-nitrosylation on various
proteins, it is noteworthy whether PDI affects S-nitrosylation of NMDAR in acute seizure and chronic
epilepsy models. In the present study, we found that acute
seizures in response to
pilocarpine and spontaneous
seizures in chronic
epilepsy rats led to the reduction in S-nitrosylated
thiol (SNO-
thiol)-to-total
thiol ratio on NMDAR, while they elevated
nitric oxide (NO) level and S-nitrosylation on NMDAR. N-nitro-
L-arginine methyl ester (
L-NAME, a non-selective NOS inhibitor) did not affect seizure activities in both models, although it decreased SNO-
thiol levels on NMDAR. However, PDI knockdown effectively inhibited
pilocarpine-induced acute
seizures and spontaneous
seizures in chronic
epilepsy rats, accompanied by increasing the SNO-
thiol-to-total
thiol ratio on NMDAR due to diminishing the amounts of total
thiols on GluN1 and GluN2A. Therefore, these findings indicate that PDI may not be a NO donor or a denitrosylase for NMDAR, and that PDI knockdown may inhibit seizure activity by the S-nitrosylation-independent thiolation on NMDAR.