Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
Department of Medicine, School of Medicine, University of California, San Diego, CA, 92093, USA.
Dig Dis Sci. 2019 Sep;64(9):2527-2537. doi: 10.1007/s10620-019-05578-7. Epub 2019 Mar 14.
Although ClC-2 channels are important in colonic Cl secretion, it is unclear about their roles in small intestinal anion secretion. Therefore, we sought to examine whether ClC-2 channels play important roles in anion secretion, particularly duodenal bicarbonate secretion (DBS).
Duodenal mucosae from mice were stripped of seromuscular layers and mounted in Ussing chambers. Both duodenal short-circuit current (I) and HCO secretion in vitro were simultaneously recorded. DBS in vivo was measured by a CO-sensitive electrode.
Lubiprostone, a selective ClC-2 activator, concentration-dependently increased both duodenal I and DBS only when applied basolaterally, but not when applied apically. Removal of extracellular Cl abolished lubiprostone-induced duodenal I, but did not alter HCO secretion even in the presence of DIDS, a Cl/HCO exchanger inhibitor. However, further addition of glibenclamide, a CFTR channel blocker, abolished lubiprostone-evoked HCO secretion. Moreover, lubiprostone-induced HCO secretion was impaired in CFTR mice compared to wild-type littermates. Luminal perfusion of duodenal lumen with lubiprostone did not alter basal DBS in vivo, but lubiprostone (i.p.) was able to induce DBS, which was also significantly inhibited by Cd, a ClC-2 channel blocker. [Ca] level, Ca-activated K channel- and cAMP-mediated duodenal I, and HCO secretion were unchanged by lubiprostone.
We have provided the first evidence for the novel functional role of basolateral ClC-2 channels in the regulation of duodenal anion secretion.
尽管 ClC-2 通道在结肠 Cl 分泌中很重要，但它们在小肠阴离子分泌中的作用尚不清楚。因此，我们试图研究 ClC-2 通道是否在阴离子分泌中发挥重要作用，特别是十二指肠碳酸氢盐分泌（DBS）。
从小鼠中分离出十二指肠黏膜，去除浆膜肌层，置于 Ussing 室中。同时记录十二指肠短电路电流（I）和体外 HCO 分泌。通过 CO 敏感电极测量体内 DBS。
选择性 ClC-2 激活剂鲁比前列酮浓度依赖性地增加了十二指肠 I 和 DBS，仅当应用于基底外侧时才增加，而当应用于顶侧时则不增加。去除细胞外 Cl 可消除鲁比前列酮诱导的十二指肠 I，但即使存在 Cl/HCO 交换抑制剂 DIDS，也不会改变 HCO 分泌。然而，进一步添加 CFTR 通道阻滞剂格列本脲则消除了鲁比前列酮诱导的 HCO 分泌。此外，与野生型同窝仔相比，CFTR 小鼠的鲁比前列酮诱导的 HCO 分泌受损。与体内基础 DBS 相比，十二指肠腔腔灌流鲁比前列酮不会改变基础 DBS，但鲁比前列酮（ip）能够诱导 DBS，这也被 ClC-2 通道阻滞剂 Cd 显著抑制。[Ca]水平、Ca 激活的 K 通道和 cAMP 介导的十二指肠 I 和 HCO 分泌不受鲁比前列酮影响。
我们首次提供了基底外侧 ClC-2 通道在调节十二指肠阴离子分泌中的新功能作用的证据。
