Premium
Basolateral Ca 2+ ‐dependent K + ‐channels play a key role in Cl—secretion induced by taurodeoxycholate from colon mucosa
Author(s) -
Moschetta Antonio,
Portincasa Piero,
Debellis Lucantonio,
Petruzzelli Michele,
Montelli Roberta,
Calamita Giuseppe,
Gustavsson Pontus,
Palasciano Giuseppe
Publication year - 2003
Publication title -
biology of the cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 85
eISSN - 1768-322X
pISSN - 0248-4900
DOI - 10.1016/s0248-4900(03)00011-x
Subject(s) - cotransporter , secretion , niflumic acid , crypt , epithelial polarity , chemistry , channel blocker , medicine , biophysics , intestinal mucosa , ion transporter , endocrinology , biology , sodium , biochemistry , calcium , cell , membrane , organic chemistry
The diarrhea associated with malabsorption of bile salts such as the secondary hydrophobic taurodeoxycholate (TDC) may be partly explained by the TDC‐induced increase in colon Cl − secretion. We, therefore, investigated the effects of TDC (0.5–8 mM) on electrical parameters and electrolyte transport of rat proximal colon mucosa mounted in Ussing chambers. Colonic secretion, measured as short circuit current ( I SC ), progressively increased on mucosal incubation with TDC ranging 0.5–2 mM; up to TDC 2 mM, a spontaneous recovery toward control values with no changes in epithelial resistance (Rt), and lactate dehydrogenase (LDH) release was observed. In contrast, for TDC > 2 mM, I SC increased further and the effect was progressive and associated with a significant decrease in the Rt and increased LDH release, implying a cytolytic effect. Mucosal preincubation with the Cl − channel inhibitor 5‐nitro‐2‐(3‐phenylpropylamino) benzoic acid (NPPB), fully prevented the precytolytic effect of TDC on I SC . Serosal preincubation with furosemide, a Na + /K + /2Cl − cotransporter inhibitor, significantly reduced TDC‐induced increase in I SC . Inhibition of the basolateral Ca 2+ ‐dependent K + channel—rSK4—with serosal clotrimazole or incubation with mucosal Ca 2+ ‐free (EGTA) buffer completely prevented precytolytic TDC‐induced increase in I SC . In conclusion, Cl − secretion is activated in colon mucosa by TDC low concentrations; while at higher concentrations, a detergent cytotoxic effect intervenes. Activation of the Ca 2+ ‐dependent basolateral K + pathway, through TDC‐induced apical Ca 2+ influx, provides the Na + /K + /2Cl − basolateral activation, thereby the driving force for the apical exit of Cl − ions. These findings further enhance the knowledge of the pathogenic mechanisms of diarrhea associated with bile salt malabsorption.