Regulation of the SIRT1 signaling pathway in NMDA-induced Excitotoxicity

Xiaorong Yang, Xuefei Sun, Jinzi Wu, Jinteng Ma, Peipei Si, Litian Yin, Yu Zhang, Liang Jun Yan, Ce Zhang

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Silent Information Regulator 1 (SIRT1), an NAD+-dependent deacetylase, contributes to the neuroprotective effect. However, intracellular signaling pathways that affect SIRT1 function remain unknown. It is well known that N-methyl-D-aspartate (NMDA) receptor activation induces calcium influx which then activates PKC, and SIRT1 is a mRNA target for HuR protein. We hypothesize that Ca2+-PKC-HuR-SIRT1 pathway modulates SIRT1 function. The present study is to investigate the potential pathway of SIRT1 in the SH-SY5Y cell line as an in vitro model of NMDA-induced neurotoxicity. The results showed that: (1) SIRT1 levels were downregulated in NMDA model; (2) NMDA induced an increase in serine phosphorylation of HuR, while inhibition of serine phosphorylation of HuR increased SIRT1 levels, promoting cell survival; (3) PKC inhibitor (Gö 6976) reversed NMDA insults and also suppressed serine phosphorylation of HuR; (4) 1,2-bis(2-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid (BAPTA-AM), an intracellular calcium chelator, fully reversed NMDA insults and also inhibited PKC activity evoked by NMDA. These results indicate that intracellular elevated Ca2+ activates PKC, which phosphorylates HuR and then promotes SIRT1 mRNA decay and subsequent neuronal death in NMDA model. Therefore, the study suggests that inhibition of Ca2+-PKC-HuR-SIRT1 pathway could be an effective strategy for preventing certain neurological diseases related to NMDA excitotoxicity.

Original languageEnglish
Pages (from-to)66-76
Number of pages11
JournalToxicology Letters
Volume322
DOIs
StatePublished - 1 Apr 2020

Keywords

  • Ca
  • Excitotoxicity
  • HuR
  • NMDA
  • PKC
  • SIRT1

Fingerprint Dive into the research topics of 'Regulation of the SIRT1 signaling pathway in NMDA-induced Excitotoxicity'. Together they form a unique fingerprint.

  • Cite this

    Yang, X., Sun, X., Wu, J., Ma, J., Si, P., Yin, L., Zhang, Y., Yan, L. J., & Zhang, C. (2020). Regulation of the SIRT1 signaling pathway in NMDA-induced Excitotoxicity. Toxicology Letters, 322, 66-76. https://doi.org/10.1016/j.toxlet.2020.01.009