The Role of Cell Membrane Information Reception, Processing, and Communication in the Structure and Function of Multicellular Tissue

Abstract

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^-, Ca²⁺, Mg²⁺) 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.

Keywords: cell membrane; distributed system; genome; information; signal conduction.

Figure 1

Information detected by the protein gate in a K+ channel in the cell membrane opens the gate allowing rapid efflux of most abundant mobile cation. (a) Baseline state with large transmembrane gradients in Na⁺, Cl⁻, and K⁺ generated by ATP-dependent membrane pumps. In the cytoplasm (K⁺), as the mobile cation with the highest concentration, is the primary shield of negative charges on the inner leaf of the cell membrane and reaction pocket of an enzyme (this neglects Ca²⁺ and Mg²⁺, which can also serve as cation shields but are present in very low concentrations). The active site of the enzyme is too large to match the shape of the substrate, and the shielding of the inner leaf of the membrane does not allow it to attract the positive charges on the peripheral membrane protein. (b) Following an external perturbation that opens the K⁺ channel, a rapid efflux of K⁺ briefly lowers the K⁺ concentration in the adjacent cytoplasm. This reduces the shield on the negative inner leaf of the cell membrane allowing positively charged peripheral membrane protein. This reduction in shielding of the inner leaf of the membrane may also cause local changes in the lipid asymmetry in the cell membrane (e.g., negatively charged phosphatidylserine normally in the inner leaf) which can alter membrane stiffness or release of lipid second messengers, such as PIP3. The change in cation concentration alters the reaction site on the enzyme so that it can now bind the adjacent substrate and catalyze the reaction. This dependence of protein function on cation concentrations has been observed empirically. We speculate a cause may be related to the smaller volume Na⁺ ions compared to K⁺ ions.

Figure 2

The role of ion dynamics in EGFR signaling. Ligand binding to EGFR activates Ras through binding of GTP (adding negative charges). Empirical data then show rapid movement, then show “Ras recruits Raf to the membrane” [43] leading to signal transduction to the nucleus along the MAPK pathways. The latter, however, provides no information of the physical mechanism. A hypothesis is that the K⁺ channel associated with EGFR opens upon ligand binding. The outflow of K⁺ reduces shield on the inner leaf of the membrane. Raf, with a pK of 9.3, is positively charged, and there are clustered positive charges on the scaffolding protein CNKSR1. These allow coulomb interactions with negative charges on the inner leaf of the cell membrane resulting in the physical movement observed experimentally.

Figure 3

An integrative model of communication from cell membrane receptors to other components of the cell. The canonical molecular pathways are amplifiers that allow signals to reach the nucleus, mitochondria, and endoplasmic reticulum. However, diffusion in three dimensions results in degradation of spatial and temporal information. The microfilaments and microtubules allow rapid, bi-directional flow ions between the cytoplasm adjacent to the cell membrane and the centrosome (via microtubules) and the nuclear membrane (via microfilaments). This permits rapid communication of both coarse-grained and fine-grained information with minimum information loss. Furthermore, the associated spatial and temporal information may be critical for survival in single-cell organisms and in the organization and function of multicellular tissue.