title: Pulses of cell Ca(2+) and the dynamics of tight junction opening and closing.
abstract: A mathematical modeling of tight junction (TJ) dynamics was elaborated in a previous study 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 Ca(2+) levels. In this model, TJs were assumed to be specifically controlled by the Ca(2+) concentration levels at the extracellular Ca(2+) 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 Ca(2+) concentration (Ca(2+) (cell)), which might result from changes \ of extracellular Ca(2+) concentration (Ca(2+) (extl)), contribute to the observed results. In order to address this aspect of TJ regulation, fast Ca(2+)-switch experiments were performed in which changes of Ca(2+) (cell) were induced using the Ca(2+) ionophore A23187 or thapsigargin, a specific inhibitor of the sarco-endoplasmic reticulum Ca(2+)-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 Ca(2+) (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 Ca(2+) (cell) never led to a decline of G, indicating that a rise of Ca(2+) (cell) does not trigger per se TJ closure. On the contrary, always the first response to a rise of Ca(2+) (cell) is an increase of G that, in most cases, is a transient response. Despite these observations we cannot assure that a rise of Ca(2+) (cell) is without effect on the TJs, since an increase of Ca(2+) (cell) not only causes a transient increase of G but, in addition, during oscillations a rise of Ca(2+) (cell) induced by the Ca(2+) ionophore transiently halted the oscillatory pattern of TJs. The main conclusion of this study is that TJ closure that is observed when basolateral Ca(2+) concentration (Ca(2+) (bl)) is increased after TJs were opened by Ca(2+) (bl) removal cannot be ascribed to a rise of Ca(2+) (cell) and might be a consequence of Ca(2+) binding to extracellular Ca(2+) sites.
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. flacaz@usp.br
authors.forename: F
authors.initials: F
authors.lastname: Lacaz-Vieira
authors.forename: M M
authors.initials: MM
authors.lastname: Marques
mesh_terms: D000818:Animals; D000001:Calcimycin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology*; D007476:Ionophores / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000502:physiology*; D011892:Rana catesbeiana; D019284:Thapsigargin / Q000494:pharmacology*; D019108:Tight Junctions / Q000187:drug effects / Q000502:physiology*; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology*; D014982:Xenopus laevis
chemical_list: D007476:Ionophores; D000001:Calcimycin; D019284:Thapsigargin; D002118:Calcium