Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305-5345, USA.
Cell. 2012 May 25;149(5):1112-24. doi: 10.1016/j.cell.2012.03.041.
Activity-dependent gene expression triggered by Ca(2+) entry into neurons is critical for learning and memory, but whether specific sources of Ca(2+) act distinctly or merely supply Ca(2+) to a common pool remains uncertain. Here, we report that both signaling modes coexist and pertain to Ca(V)1 and Ca(V)2 channels, respectively, coupling membrane depolarization to CREB phosphorylation and gene expression. Ca(V)1 channels are advantaged in their voltage-dependent gating and use nanodomain Ca(2+) to drive local CaMKII aggregation and trigger communication with the nucleus. In contrast, Ca(V)2 channels must elevate Ca(2+) microns away and promote CaMKII aggregation at Ca(V)1 channels. Consequently, Ca(V)2 channels are ~10-fold less effective in signaling to the nucleus than are Ca(V)1 channels for the same bulk Ca(2+) increase. Furthermore, Ca(V)2-mediated Ca(2+) rises are preferentially curbed by uptake into the endoplasmic reticulum and mitochondria. This source-biased buffering limits the spatial spread of Ca(2+), further attenuating Ca(V)2-mediated gene expression.
神经元内钙离子内流引发的活性依赖基因表达对学习和记忆至关重要，但特定的钙离子来源是分别起作用，还是仅为共同的钙离子池提供钙离子，目前仍不确定。在这里，我们报告说，这两种信号模式同时存在，分别与 Ca(V)1 和 Ca(V)2 通道相关，分别将膜去极化与 CREB 磷酸化和基因表达偶联。Ca(V)1 通道在其电压依赖性门控方面具有优势，并利用纳米域钙离子驱动局部 CaMKII 聚集，并触发与核的通讯。相比之下，Ca(V)2 通道必须在微米之外升高 Ca(2+)，并促进 CaMKII 在 Ca(V)1 通道上的聚集。因此，对于相同的总体 Ca(2+)增加，Ca(V)2 通道向核的信号传递效率比 Ca(V)1 通道低约 10 倍。此外，Ca(V)2 介导的钙离子上升优先被内质网和线粒体摄取所抑制。这种源偏向性缓冲限制了钙离子的空间扩散，进一步减弱了 Ca(V)2 介导的基因表达。
