Tissue barriers that restrict passage of liquids, ions, and larger solutes are essential for the development of multicellular organisms. In simple organisms this allows distinct cell types to interface with the external environment. In more complex species, the diversity of cell types capable of forming barriers increases dramatically. Although the plasma membranes of these barrier-forming cells prevent flux of most hydrophilic solutes, the paracellular, or shunt, pathway between cells must also be sealed. This function is accomplished in vertebrates by the zonula occludens, or tight junction. The tight junction barrier is not absolute but is selectively permeable and is able to discriminate between solutes on the basis of size and charge. Many tight junction components have been identified over the past 20 years, and recent progress has provided new insights into the proteins and interactions that regulate structure and function. This review presents these data in a historical context and proposes an integrated model in which dynamic regulation of tight junction protein interactions determines barrier function.

We have developed a detailed mathematical model for Ca2+ handling and ionic currents in the rabbit ventricular myocyte. The objective was to develop a model that: 1), accurately reflects Ca-dependent Ca release; 2), uses realistic parameters, particularly those that concern Ca transport from the cytosol; 3), comes to steady state; 4), simulates basic excitation-contraction coupling phenomena; and 5), runs on a normal desktop computer. The model includes the following novel features: 1), the addition of a subsarcolemmal compartment to the other two commonly formulated cytosolic compartments (junctional and bulk) because ion channels in the membrane sense ion concentrations that differ from bulk; 2), the use of realistic cytosolic Ca buffering parameters; 3), a reversible sarcoplasmic reticulum (SR) Ca pump; 4), a scheme for Na-Ca exchange transport that is [Na]i dependent and allosterically regulated by [Ca]i; and 5), a practical model of SR Ca release including both inactivation/adaptation and SR Ca load dependence. The data describe normal electrical activity and Ca handling characteristics of the cardiac myocyte and the SR Ca load dependence of these processes. The model includes a realistic balance of Ca removal mechanisms (e.g., SR Ca pump versus Na-Ca exchange), and the phenomena of rest decay and frequency-dependent inotropy. A particular emphasis is placed upon reproducing the nonlinear dependence of gain and fractional SR Ca release upon SR Ca load. We conclude that this model is more robust than many previously existing models and reproduces many experimental results using parameters based largely on experimental measurements in myocytes.

Abstract-Depressed contractility is a central feature of the failing human heart and has been attributed to altered [Ca 2ϩ

The tight junction defines epithelial organization. Structurally, the tight junction is comprised of transmembrane and membrane-associated proteins that are thought to assemble into stable complexes to determine function. In this study, we measure tight junction protein dynamics in live confluent Madin–Darby canine kidney monolayers using fluorescence recovery after photobleaching and related methods. Mathematical modeling shows that the majority of claudin-1 (76 ± 5%) is stably localized at the tight junction. In contrast, the majority of occludin (71 ± 3%) diffuses rapidly within the tight junction with a diffusion constant of 0.011 μm2s−1. Zonula occludens-1 molecules are also highly dynamic in this region, but, rather than diffusing within the plane of the membrane, 69 ± 5% exchange between membrane and intracellular pools in an energy-dependent manner. These data demonstrate that the tight junction undergoes constant remodeling and suggest that this dynamic behavior may contribute to tight junction assembly and regulation.