Hou Hailong, Chávez Andrés E, Wang Chih-Chieh, Yang Hongtian, Gu Hua, Siddoway Benjamin A, Hall Benjamin J, Castillo Pablo E, Xia Houhui
Neuroscience Center and.
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, and.
J Neurosci. 2014 Oct 15;34(42):14006-12. doi: 10.1523/JNEUROSCI.1659-14.2014.
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.
NMDA受体信号传导在CREB激活和CREB介导的基因转录中发挥着复杂的作用，这取决于NMDA受体的亚细胞定位以及它们被激活的强度。然而，尚不清楚Rac GTP酶的原型Rac1是否在NMDA受体信号传导诱导的神经元CREB激活中发挥作用。在此，我们报告，广泛使用的特异性Rac1抑制剂NSC23766可抑制大鼠皮质神经元中S133位点的基础CREB磷酸化（pCREB），并拮抗NMDA浴应用诱导的pCREB水平变化。出乎意料的是，我们发现NSC23766以Rac1非依赖的方式影响神经元pCREB的水平。相反，我们的结果表明，NSC23766可以直接调节NMDA受体，这分别通过其对小鼠和大鼠神经元中外源性和突触诱发的NMDA受体介导电流的强烈影响得以体现。我们的研究结果强烈表明，Rac1不影响皮质神经元中的pCREB信号传导，并揭示NSC23766可能是一种新型的NMDA受体拮抗剂。
