Department of Neurobiology and Anatomy, University of Texas Medical School, Houston, Texas, USA.
PLoS Comput Biol. 2010 Nov 11;6(11):e1000987. doi: 10.1371/journal.pcbi.1000987.
Calmodulin (CaM) is a ubiquitous Ca(2+) buffer and second messenger that affects cellular function as diverse as cardiac excitability, synaptic plasticity, and gene transcription. In CA1 pyramidal neurons, CaM regulates two opposing Ca(2+)-dependent processes that underlie memory formation: long-term potentiation (LTP) and long-term depression (LTD). Induction of LTP and LTD require activation of Ca(2+)-CaM-dependent enzymes: Ca(2+)/CaM-dependent kinase II (CaMKII) and calcineurin, respectively. Yet, it remains unclear as to how Ca(2+) and CaM produce these two opposing effects, LTP and LTD. CaM binds 4 Ca(2+) ions: two in its N-terminal lobe and two in its C-terminal lobe. Experimental studies have shown that the N- and C-terminal lobes of CaM have different binding kinetics toward Ca(2+) and its downstream targets. This may suggest that each lobe of CaM differentially responds to Ca(2+) signal patterns. Here, we use a novel event-driven particle-based Monte Carlo simulation and statistical point pattern analysis to explore the spatial and temporal dynamics of lobe-specific Ca(2+)-CaM interaction at the single molecule level. We show that the N-lobe of CaM, but not the C-lobe, exhibits a nano-scale domain of activation that is highly sensitive to the location of Ca(2+) channels, and to the microscopic injection rate of Ca(2+) ions. We also demonstrate that Ca(2+) saturation takes place via two different pathways depending on the Ca(2+) injection rate, one dominated by the N-terminal lobe, and the other one by the C-terminal lobe. Taken together, these results suggest that the two lobes of CaM function as distinct Ca(2+) sensors that can differentially transduce Ca(2+) influx to downstream targets. We discuss a possible role of the N-terminal lobe-specific Ca(2+)-CaM nano-domain in CaMKII activation required for the induction of synaptic plasticity.
钙调蛋白（CaM）是一种普遍存在的 Ca(2+) 缓冲剂和第二信使，它影响着从心脏兴奋性、突触可塑性到基因转录等多种细胞功能。在 CA1 锥体神经元中，CaM 调节着记忆形成所必需的两种相反的 Ca(2+)-依赖性过程：长时程增强（LTP）和长时程抑制（LTD）。LTP 和 LTD 的诱导需要激活 Ca(2+)-CaM 依赖性酶：Ca(2+)/CaM 依赖性激酶 II（CaMKII）和钙调神经磷酸酶，分别。然而，Ca(2+) 和 CaM 如何产生这两种相反的效应，LTP 和 LTD，仍然不清楚。CaM 结合 4 个 Ca(2+) 离子：两个在其 N 端结构域，两个在其 C 端结构域。实验研究表明，CaM 的 N 端和 C 端结构域对 Ca(2+) 及其下游靶标具有不同的结合动力学。这可能表明 CaM 的每个结构域对 Ca(2+) 信号模式有不同的反应。在这里，我们使用一种新的事件驱动的基于粒子的蒙特卡罗模拟和统计点模式分析来探索 Ca(2+)-CaM 相互作用在单分子水平上的空间和时间动力学。我们表明，CaM 的 N 端结构域，但不是 C 端结构域，表现出高度敏感于 Ca(2+) 通道位置和 Ca(2+) 离子微观注入率的纳米级激活域。我们还证明，Ca(2+) 饱和是通过两种不同的途径发生的，这取决于 Ca(2+) 注入率，一种由 N 端结构域主导，另一种由 C 端结构域主导。总之，这些结果表明 CaM 的两个结构域作为不同的 Ca(2+) 传感器发挥作用，可以将 Ca(2+) 流入下游靶标进行差异转导。我们讨论了 N 端结构域特异性 Ca(2+)-CaM 纳米域在诱导突触可塑性所需的 CaMKII 激活中的可能作用。
