Cohen Samuel M, Li Boxing, Tsien Richard W, Ma Huan
NYU Neuroscience Institute and Department of Neuroscience and Physiology, NYU Langone Medical Center, New York, NY 10016, USA.
NYU Neuroscience Institute and Department of Neuroscience and Physiology, NYU Langone Medical Center, New York, NY 10016, USA.
Biochem Biophys Res Commun. 2015 Apr 24;460(1):88-99. doi: 10.1016/j.bbrc.2015.02.146.
Reliance on Ca(2+) signaling has been well-preserved through the course of evolution. While the complexity of Ca(2+) signaling pathways has increased, activation of transcription factors including CREB by Ca(2+)/CaM-dependent kinases (CaMKs) has remained critical for long-term plasticity. In C. elegans, the CaMK family is made up of only three members, and CREB phosphorylation is mediated by CMK-1, the homologue of CaMKI. CMK-1 nuclear translocation directly regulates adaptation of thermotaxis behavior in response to changes in the environment. In mammals, the CaMK family has been expanded from three to ten members, enabling specialization of individual elements of a signal transduction pathway and increased reliance on the CaMKII subfamily. This increased complexity enables private line communication between Ca(2+) sources at the cell surface and specific cellular targets. Using both new and previously published data, we review the mechanism of a γCaMKII-CaM nuclear translocation. This intricate pathway depends on a specific role for multiple Ca(2+)/CaM-dependent kinases and phosphatases: α/βCaMKII phosphorylates γCaMKII to trap CaM; CaN dephosphorylates γCaMKII to dispatch it to the nucleus; and PP2A induces CaM release from γCaMKII so that CaMKK and CaMKIV can trigger CREB phosphorylation. Thus, while certain basic elements have been conserved from C. elegans, evolutionary modifications offer opportunities for targeted communication, regulation of key nodes and checkpoints, and greater specificity and flexibility in signaling.
在进化过程中，对钙信号的依赖一直得以很好地保留。虽然钙信号通路的复杂性有所增加，但包括CREB在内的转录因子由钙/钙调蛋白依赖性激酶（CaMKs）激活对于长期可塑性仍然至关重要。在秀丽隐杆线虫中，CaMK家族仅由三个成员组成，CREB磷酸化由CaMKI的同源物CMK-1介导。CMK-1的核转位直接调节趋温行为对环境变化的适应性。在哺乳动物中，CaMK家族已从三个成员扩展到十个成员，使得信号转导通路的各个元件得以专门化，并增加了对CaMKII亚家族的依赖。这种增加的复杂性使得细胞表面的钙源与特定细胞靶点之间能够进行专线通信。利用新的和先前发表的数据，我们综述了γCaMKII-CaM核转位的机制。这条复杂的途径依赖于多种钙/钙调蛋白依赖性激酶和磷酸酶的特定作用：α/βCaMKII磷酸化γCaMKII以捕获钙调蛋白；钙调神经磷酸酶使γCaMKII去磷酸化以便将其发送到细胞核；而蛋白磷酸酶2A诱导钙调蛋白从γCaMKII释放，从而使钙调蛋白激酶激酶和CaMKIV能够触发CREB磷酸化。因此，虽然某些基本元件在秀丽隐杆线虫中得以保留，但进化修饰为靶向通信、关键节点和检查点的调节以及信号传导中更高的特异性和灵活性提供了机会。
