Protein synthesis in response to neuronal activity, known as activity-dependent translation, is critical for synaptic plasticity and memory formation. However, the signaling cascades that couple neuronal activity to the translational events remain elusive. In this study, we identified the role of calmodulin (CaM), a conserved Ca²⁺-binding protein, in ribosomal RNA (rRNA) biogenesis in neurons. We found the CaM-regulated rRNA synthesis is Ca²⁺-dependent and necessary for nascent protein synthesis and axon growth in hippocampal neurons. Mechanistically, CaM interacts with nucleolar DEAD (Asp–Glu–Ala–Asp) box RNA helicase (DDX21) in a Ca²⁺-dependent manner to regulate nascent rRNA transcription within nucleoli. We further found CaM alters the conformation of DDX21 to liberate the DDX21-sequestered RPA194, the catalytic subunit of RNA polymerase I, to facilitate transcription of ribosomal DNA. Using high-throughput screening, we identified the small molecules batefenterol and indacaterol that attenuate the CaM-DDX21 interaction and suppress nascent rRNA synthesis and axon growth in hippocampal neurons. These results unveiled the previously unrecognized role of CaM as a messenger to link the activity-induced Ca²⁺ influx to the nucleolar events essential for protein synthesis. We thus identified the ability of CaM to transmit information to the nucleoli of neurons in response to stimulation.

响应神经元活动的蛋白质合成，称为活动依赖性翻译，对于突触可塑性和记忆形成至关重要。然而，将神经元活动与翻译事件耦合的信号级联仍然难以捉摸。在这项研究中，我们确定了钙调蛋白 (CaM)（一种保守的 Ca ²⁺结合蛋白）在神经元核糖体 RNA (rRNA) 生物合成中的作用。我们发现 CaM 调节的 rRNA 合成是 Ca ²⁺依赖性的，并且是海马神经元新生蛋白质合成和轴突生长所必需的。从机制上讲，CaM 以 Ca ²⁺依赖性方式与核仁 DEAD (Asp-Glu-Ala-Asp) 盒 RNA 解旋酶 (DDX21) 相互作用，调节核仁内新生 rRNA 转录。我们进一步发现 CaM 改变 DDX21 的构象，释放 DDX21 隔离的 RPA194（RNA 聚合酶 I 的催化亚基），以促进核糖体 DNA 的转录。通过高通量筛选，我们鉴定出了小分子巴特芬特罗和茚达特罗，它们可以减弱 CaM-DDX21 相互作用并抑制海马神经元中新生 rRNA 合成和轴突生长。这些结果揭示了 CaM 作为信使的作用，该信使将活性诱导的 Ca ²⁺流入与蛋白质合成所必需的核仁事件联系起来。因此，我们确定了 CaM 响应刺激而将信息传递到神经元核仁的能力。