title: The Rac1 inhibitor NSC23766 suppresses CREB signaling by targeting NMDA receptor function.
abstract: 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.
authors.affiliation: Neuroscience Center and.
authors.forename: Hailong
authors.initials: H
authors.lastname: Hou
authors.affiliation: Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, and.
authors.forename: Andrés E
authors.identifier: http://orcid.org/0000-0001-8795-9238
authors.initials: AE
authors.lastname: Chávez
authors.affiliation: Neuroscience Program and.
authors.forename: Chih-Chieh
authors.initials: CC
authors.lastname: Wang
authors.affiliation: Neuroscience Center and.
authors.forename: Hongtian
authors.initials: H
authors.lastname: Yang
authors.affiliation: Neuroscience Center and.
authors.forename: Hua
authors.initials: H
authors.lastname: Gu
authors.affiliation: Neuroscience Center and.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Siddoway
authors.affiliation: Neuroscience Program and Departments of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana 70118.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Hall
authors.affiliation: Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, and.
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Castillo
authors.affiliation: Neuroscience Center and Department of Cell Biology and Anatomy, LSU Health Science Center, New Orleans, Louisiana 70112, hxia@lsuhsc.edu.
authors.forename: Houhui
authors.initials: H
authors.lastname: Xia
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D008297:Male; D009924:Organ Culture Techniques; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D017362:Cyclic AMP Response Element-Binding Protein; C487513:NSC 23766; D011743:Pyrimidines; D016194:Receptors, N-Methyl-D-Aspartate; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein
keywords: CREB; NMDA receptor; NSC23766; Rac1; antagonist