Taurodeoxycholic acid stimulates cholangiocyte potassium channels
Dijanic, Amanda T.
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Liver bile duct epithelial cells (cholangiocytes) are responsible for producing the HCO 3 -rich solution which alkalinizes bile and promotes bile flow to the duodenum. Basolateral membrane K + channels found in cholangiocytes provide the driving force for Cl - secretion which drives HCO 3 - and fluid secretion. The central hypothesis of this work is that the basolateral membrane K + channels found in cholangiocytes are KCNQ1-KCNE3 K + channels and are stimulated by taurodeoxycholic acid (TDC), a secondary dihydroxy conjugated bile acid. The mechanisms by which TDC activates KCNQ1-KCNE3 K + channels are unknown. Cultured human Mz-ChA-1 cells and KCNQ1-KCNE3 transfected Xenopus oocytes were used to conduct our study. TDC was found to stimulate K + currents in a temperature- and dose dependent manner in whole-cell patch-clamp experiments. These currents were reversibly inhibited by Ba 2+ ion. Rp-cAMPS, a cAMP analog and antagonist to the cAMP pathway, did not significantly inhibit these K + currents; however, more data may be needed for conclusive results. Ratiometric measurements using FURA2-AM Ca 2+ imaging conclusively showed that TDC does not activate K + current in Mz-ChA-1 cells via a Ca 2+ -mediated pathway. Two-electrode voltage-clamp measurements on KCNQ1-KCNE3 transfected oocytes revealed that low concentrations of TDC have no effect on K + current amplitude; however, 1 mM TDC caused an apparent inactivation of the KCNQ1-KCNE3 current. This is a novel observation since KCNQ1-KCNE3 is a constitutively open channel. Overall, these data suggest TDC may act through a cAMP-mediated pathway; however, more investigation is needed to confirm this hypothesis.