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Thapsigargin, a new calcium‐dependent epithelial anion secretagogue
Author(s) -
Brayden D.J.,
Hanley M.R.,
Thastrup O.,
Cuthbert A.W.
Publication year - 1989
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1989.tb14609.x
Subject(s) - thapsigargin , calcium , chemistry , secretagogue , biophysics , endocrinology , medicine , secretion , biochemistry , biology , organic chemistry
1 Thapsigargin, a sesquiterpene lactone, was shown to cause electrogenic anion secretion in monolayers of human colonic epithelial cells, an effect which was crucially dependent upon calcium and did not involve eicosanoid formation. 2 To measure the secretory effect calcium needed to be present in the external bathing solution. By means of Fura‐2 fluorescence measurements thapsigargin was shown to raise Ca i by around 250 n m when the bathing solution contained calcium. In the nominal absence of external calcium thapsigargin raised Ca i by only 60 n m , but from a lower basal value. This was insufficient to cause secretion. 3 Effects of other calcium‐dependent secretagogues (e.g. lysylbradykinin) were inhibited in the presence of thapsigargin, whereas kinin responses were potentiated if the peptide was added following a stimulus which increases cyclic AMP. 4 From the data given here and the known behaviour of colonic epithelia it is concluded that thapsigargin increases Ca i by a non‐ionophoric mechanism by release from internal stores. Calcium‐stimulated calcium influx then follows resulting in the opening of basolateral K channels, increasing the electrochemical gradient for chloride efflux, or alternatively by activating anion channels in the apical membrane. It is concluded that thapsigargin is a potentially important tool for examining epithelial mechanisms.