Involvement of intracellular and extracellular Ca2+ in tetramethylpyrazine‐induced colonic anion secretion

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Abstract
In the present study we investigated the role of Ca2+ in tetramethylpyrazine (TMP)‐induced anion secretion in the human colonic epithelial cell line, Caco‐2, using the short‐circuit current (ISC) technique in conjunction with intracellular Ca2+ measurements. The results showed that TMP‐induced ISC response was significantly reduced by 58.8% and 38.3% after inhibiting Ca2+ ATPase of endoplasmic reticulum (ER) with thapsigargin and mobilizing ER stored Ca2+ release with ATP, respectively. Conversely, thapsigargin‐ and ATP‐evoked ISC responses were also significantly reduced by pretreatment with TMP by 43.2% and 38.5%, respectively. Conversely, removal of extracellular Ca2+, apical but not basolateral, or the presence of the Ca2+ chelator (EGTA) significantly increased TMP‐induced ISC by 47.1% and 37.8%, respectively. Similar to TMP, thapsigargin‐induced current increase was also enhanced by chelating extracellular Ca2+ or in Ca2+ free solution; however, removal of extracellular Ca2+ did not significantly affect 3‐isobutyl‐1‐methylxanthine (IBMX)‐ and forskolin‐induced transepithelial current. Measurement of the intracellular concentration of free Ca2+ ([Ca2+]i) with fura‐2/AM showed that TMP could induce an increase in [Ca2+]i but pretreatment with TMP significantly reduced thapsigargin‐evoked, but not ATP‐induced, [Ca2+]i increase. These results suggest that the effect of TMP on colonic anion secretion is partly mediated by TMP‐increased [Ca2+]i by acting on a target similar to thapsigargin. The observed inhibitory effect of extracellular Ca2+ on Ca2+‐dependent anion secretion represents a novel mechanism by which Ca2+‐dependent regulation of epithelial electrolyte transport may be fine‐tuned by extracellular Ca2+ in the apical domain.

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