Departments of Radiology and Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA.
Int J Mol Sci. 2019 Jul 24;20(15):3609. doi: 10.3390/ijms20153609.
Investigations of information dynamics in eukaryotic cells focus almost exclusively on heritable information in the genome. Gene networks are modeled as "central processors" that receive, analyze, and respond to intracellular and extracellular signals with the nucleus described as a cell's control center. Here, we present a model in which cellular information is a distributed system that includes non-genomic information processing in the cell membrane that may quantitatively exceed that of the genome. Within this model, the nucleus largely acts a source of macromolecules and processes information needed to synchronize their production with temporal variations in demand. However, the nucleus cannot produce microsecond responses to acute, life-threatening perturbations and cannot spatially resolve incoming signals or direct macromolecules to the cellular regions where they are needed. In contrast, the cell membrane, as the interface with its environment, can rapidly detect, process, and respond to external threats and opportunities through the large amounts of potential information encoded within the transmembrane ion gradient. Our model proposes environmental information is detected by specialized protein gates within ion-specific transmembrane channels. When the gate receives a specific environmental signal, the ion channel opens and the received information is communicated into the cell via flow of a specific ion species (i.e., K, Na, Cl, Ca, Mg) along electrochemical gradients. The fluctuation of an ion concentration within the cytoplasm adjacent to the membrane channel can elicit an immediate, local response by altering the location and function of peripheral membrane proteins. Signals that affect a larger surface area of the cell membrane and/or persist over a prolonged time period will produce similarly cytoplasmic changes on larger spatial and time scales. We propose that as the amplitude, spatial extent, and duration of changes in cytoplasmic ion concentrations increase, the information can be communicated to the nucleus and other intracellular structure through ion flows along elements of the cytoskeleton to the centrosome (via microtubules) or proteins in the nuclear membrane (via microfilaments). These dynamics add spatial and temporal context to the more well-recognized information communication from the cell membrane to the nucleus following ligand binding to membrane receptors. Here, the signal is transmitted and amplified through transduction by the canonical molecular (e.g., Mitogen Activated Protein Kinases (MAPK) pathways. Cytoplasmic diffusion allows this information to be broadly distributed to intracellular organelles but at the cost of loss of spatial and temporal information also contained in ligand binding.
真核细胞中的信息动力学研究几乎完全集中在基因组中的可遗传信息上。基因网络被建模为“中央处理器”，它们接收、分析和响应细胞内和细胞外信号，核被描述为细胞的控制中心。在这里，我们提出了一个模型，其中细胞信息是一个分布式系统，包括细胞膜中的非基因组信息处理，其数量可能超过基因组。在这个模型中，核主要充当大分子的来源，并处理将其产生与需求的时间变化同步所需的信息。然而，核不能对急性、危及生命的干扰做出微秒级的反应，也不能在空间上解析传入信号或指导大分子到需要它们的细胞区域。相比之下，细胞膜作为与环境的接口，可以通过跨膜离子梯度内编码的大量潜在信息，快速检测、处理和响应外部威胁和机会。我们的模型提出，环境信息是通过离子特异性跨膜通道中的专门蛋白门检测到的。当门接收到特定的环境信号时，离子通道打开，接收到的信息通过特定离子种类（即 K、Na、Cl、Ca、Mg）沿电化学梯度流入细胞。膜通道附近细胞质中离子浓度的波动可以通过改变外围膜蛋白的位置和功能来立即产生局部反应。影响细胞膜更大表面积的信号和/或持续更长时间的信号将在更大的空间和时间尺度上产生类似的细胞质变化。我们提出，随着细胞质中离子浓度变化的幅度、空间范围和持续时间的增加，信息可以通过离子沿着细胞骨架的元件流到中心体（通过微管）或核膜中的蛋白质（通过微丝）传递到核和其他细胞内结构。这些动态为从细胞膜到核的更广泛认可的信息传递增加了空间和时间上下文，这是在配体与膜受体结合后发生的。在这里，信号通过经典分子（例如丝裂原活化蛋白激酶（MAPK）途径）的转导进行传递和放大。细胞质扩散允许将信息广泛分布到细胞内细胞器，但代价是失去配体结合中包含的空间和时间信息。
