Department of Neuroscience & Physiology, Druckenmiller Neuroscience Institute, New York University School of Medicine, Langone Medical Center, New York, New York 10016, Center for Neural Science, New York University, New York, New York 10003, Department of Psychology, Excelsior College, Albany, New York 12203, and Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
J Neurosci. 2013 Oct 23;33(43):16930-44. doi: 10.1523/JNEUROSCI.3513-12.2013.
Regulator of calcineurin 1 (RCAN1) controls the activity of calcium/calmodulin-dependent phosphatase calcineurin (CaN), which has been implicated in human anxiety disorders. Previously, we reported that RCAN1 functioned as an inhibitor of CaN activity in the brain. However, we now find enhanced phosphorylation of a CaN substrate, cAMP response element-binding protein (CREB), in the brains of Rcan1 knock-out (KO) mice. Consistent with enhanced CREB activation, we also observe enhanced expression of a CREB transcriptional target, brain-derived neurotrophic factor (BDNF) in Rcan1 KO mice. We also discovered that RCAN1 deletion or blockade of RCAN1-CaN interaction reduced CaN and protein phosphatase-1 localization to nuclear-enriched protein fractions and promoted CREB activation. Because of the potential links between CREB, BDNF, and anxiety, we examined the role of RCAN1 in the expression of innate anxiety. Rcan1 KO mice displayed reduced anxiety in several tests of unconditioned anxiety. Acute pharmacological inhibition of CaN rescued these deficits while transgenic overexpression of human RCAN1 increased anxiety. Finally, we found that Rcan1 KO mice lacked the early anxiogenic response to the selective serotonin reuptake inhibitor (SSRI) fluoxetine and had improved latency for its therapeutic anxiolytic effects. Together, our study suggests that RCAN1 plays an important role in the expression of anxiety-related and SSRI-related behaviors through CaN-dependent signaling pathways. These results identify RCAN1 as a mediator of innate emotional states and possible therapeutic target for anxiety.
钙调神经磷酸酶 1（RCAN1）调节剂控制钙/钙调蛋白依赖性磷酸酶钙调神经磷酸酶（CaN）的活性，CaN 已被牵连到人类焦虑症中。之前，我们报道 RCAN1 在大脑中作为 CaN 活性的抑制剂发挥作用。然而，我们现在发现 Rcan1 敲除（KO）小鼠大脑中的 CaN 底物环磷酸腺苷反应元件结合蛋白（CREB）磷酸化增强。与增强的 CREB 激活一致，我们还观察到 Rcan1 KO 小鼠中 CREB 转录靶标脑源性神经营养因子（BDNF）的表达增强。我们还发现 RCAN1 缺失或阻断 RCAN1-CaN 相互作用会减少 CaN 和蛋白磷酸酶-1 向富含核蛋白的级分的定位，并促进 CREB 激活。由于 CREB、BDNF 和焦虑之间存在潜在联系，我们研究了 RCAN1 在先天焦虑表达中的作用。在几种非条件性焦虑测试中，Rcan1 KO 小鼠表现出焦虑减轻。CaN 的急性药理学抑制挽救了这些缺陷，而人 RCAN1 的转基因过表达增加了焦虑。最后，我们发现 Rcan1 KO 小鼠缺乏选择性 5-羟色胺再摄取抑制剂（SSRI）氟西汀的早期致焦虑反应，并且其治疗性抗焦虑作用的潜伏期改善。总之，我们的研究表明，RCAN1 通过 CaN 依赖性信号通路在焦虑相关和 SSRI 相关行为的表达中发挥重要作用。这些结果表明 RCAN1 是先天情绪状态的调节剂，也是焦虑的可能治疗靶点。
