The Rac1 inhibitor NSC23766 suppresses CREB signaling by targeting NMDA receptor function

Hailong Hou, Andres E. Chavez, Chih Chieh Wang, Hongtian Yang, Hua Gu, Benjamin A. Siddoway, Benjamin J. Hall, Pablo E. Castillo, Houhui Xia

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


NMDA receptor signaling plays a complex role in CREB activation and CREB-mediated gene transcription, depending on the subcellular location of NMDA receptors, as well as how strongly they are activated. However, it is not known whether Rac1, the prototype of Rac GTPase, plays a role in neuronal CREB activation induced by NMDA receptor signaling. Here, we report that NSC23766, a widely used specific Rac1 inhibitor, inhibits basal CREB phosphorylation at S133 (pCREB) and antagonizes changes in pCREB levels induced by NMDA bath application in rat cortical neurons. Unexpectedly, we found that NSC23766 affects the levels of neuronal pCREB in a Rac1-independent manner. Instead, our results indicate that NSC23766 can directly regulate NMDA receptors as indicated by their strong effects on both exogenous and synaptically evoked NMDA receptor-mediated currents in mouse and rat neurons, respectively. Our findings strongly suggest that Rac1 does not affect pCREB signaling in cortical neurons and reveal that NSC23766 could be a novel NMDA receptor antagonist.

Original languageEnglish (US)
Pages (from-to)14006-14012
Number of pages7
JournalJournal of Neuroscience
Issue number42
StatePublished - Oct 15 2014


  • Antagonist
  • CREB
  • NMDA receptor
  • NSC23766
  • Rac1

ASJC Scopus subject areas

  • General Neuroscience


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