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Pulses of Cell Ca2+ and the Dynamics of Tight Junction Opening and Closing

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Abstract

A mathematical modeling of tight junction (TJ) dynamics was elaborated in a previous study (Kassab, F., Marques, R.P., Lacaz-Vieira, F. 2002. Modeling tight junction dynamics and oscillations. J. Gen. Physiol. 120:237–247) to better understand the dynamics of TJ opening and closing, as well as oscillations of TJ permeability that are observed in response to changes of extracellular Ca2+ levels. In this model, TJs were assumed to be specifically controlled by the Ca2+ concentration levels at the extracellular Ca2+ binding sites of zonula adhaerens. Despite the fact that the model predicts all aspects of TJ dynamics, we cannot rule out the likelihood that changes of intracellular Ca2+ concentration (Ca2+ cell), which might result from changes \ of extracellular Ca2+ concentration (Ca2+ extl), contribute to the observed results. In order to address this aspect of TJ regulation, fast Ca2+-switch experiments were performed in which changes of Ca2+ cell were induced using the Ca2+ ionophore A23187 or thapsigargin, a specific inhibitor of the sarco-endoplasmic reticulum Ca2+-ATPase. The results indicate that the ionophore or thapsigargin per se do not affect basal tissue electrical conductance (G), showing that the sealing of TJs is not affected by a rise in Ca2+ cell. When TJs were kept in a dynamic state, as partially open structures or in oscillation, conditions in which the junctions are very sensitive to disturbances that affect their regulation, a rise of Ca2+ cell never led to a decline of G, indicating that a rise of Ca2+ cell does not trigger per se TJ closure. On the contrary, always the first response to a rise of Ca2+ cell is an increase of G that, in most cases, is a transient response. Despite these observations we cannot assure that a rise of Ca2+ cell is without effect on the TJs, since an increase of Ca2+ cell not only causes a transient increase of G but, in addition, during oscillations a rise of Ca2+ cell induced by the Ca2+ ionophore transiently halted the oscillatory pattern of TJs. The main conclusion of this study is that TJ closure that is observed when basolateral Ca2+ concentration (Ca2+ bl) is increased after TJs were opened by Ca2+ bl removal cannot be ascribed to a rise of Ca2+ cell and might be a consequence of Ca2+ binding to extracellular Ca2+ sites.

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Authors and Affiliations

  1. Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

    F. Lacaz-Vieira

  2. Department of Operative Dentistry, School of Dentistry, University of São Paulo, São Paulo, Brazil

    M. M. Marques

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  1. F. Lacaz-Vieira
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Correspondence to F. Lacaz-Vieira.

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Lacaz-Vieira, F., Marques, M. Pulses of Cell Ca2+ and the Dynamics of Tight Junction Opening and Closing . J. Membrane Biol. 196, 117–127 (2003). https://doi.org/10.1007/s00232-003-0630-2

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