胰管细胞HCO_3^-分泌：囊性纤维化跨膜电导调节体和SLC26转运体(英文)

Cystic fibrosis transmembrane conductance regulator and SLC26 transporters in HCO_3^- secretion by pancreatic duct cells

胰管细胞以至少6倍浓度差逆向分泌HCO_3^-(人体浓度约140 mmol/L)。HCO_3^-跨顶膜转运的可能机制包括SLC26阴离子转运体的Cl^--HCO_3^-交换和囊性纤维化跨膜电导调节体(cystic fibrosis transmembrane conductance regulator,CFTR)对HCO_3^-的传导扩散。SLC26家族成员介导上皮顶膜Cl^--HCO_3^-交换,胰管中检测到SLC26A6和SLC26A3。共表达研究揭示,鼠类slc26a6和slc26a3通过slc26的STAS结构域与CFTR的R结构域相互作用,导致活性互相增强。研究显示这些交换体是产电的:slc26a6介导ICl^--2HCO_3^-交换,slc26a3介导2Cl^--1HCO_3^-交换。近期slc26a6-/-小鼠离体胰管研究显示,slc26a6介导大部分Cl^-依赖的HCO_3^-跨顶膜分泌,与slc26a6的产电性一致。然而,因为人体能分泌非常高浓度的HCO3^-,SLC26A6在胰管HCO_3^-分泌中的作用并不十分清楚。SLC26A6的作用只能在与人类似能分泌约140 mmol/L HCO_3^-的物种,如豚鼠中研究。现有的豚鼠研究数据显示,像slc26a6介导的ICl^--2HCO_3^-交换不可能完成这种高浓度差的HCO_3^-分泌。另一方面,CFTR的HCO_3^-电导性可以在理论上支持HCO_3^-逆向分泌。所以,在豚鼠和人胰腺HCO_3^-的分泌中,CFTR可能比SLC26A6发挥更大作用。

Pancreatic duct cells secrete HCO3^- ions into a HCO36^--rich luminal fluid （-140 mmol/L in human） against at least a 6-fold concentration gradient. Candidate mechanisms for HCO3^- transport across the apical membrane include CI^--HCO3^- exchange by an SLC26 anion transporter and diffusion via the HCO3^- conductance of cystic fibrosis transmembrane conductance regulator （CFTR） Members of the SLC26 family are known to mediate CI^--HCO3^- exchange across the apical membrane of other epithelia and botl SLC26A6 and SLC26A3 have been detected in pancreatic ducts. Co-expression studies have also revealed that murine slc26a6 ant slc26a3 physically interact with CFTR through the STAS domain of slc26 and the R domain of CFTR, resulting in mutually enhanced activity. Other studies have indicated that these exchangers are electrogenic： slc26a6 mediating 1CI^--2HCO3^- exchange and slc26a.＂ mediating 2Cl^--1HCO3^- exchange. Recent experiments using isolated pancreatic ducts from slc26a6^-/- mice suggest that slc26a6 mediates most of the Cl^--dependent secretion of HCO3^- across the apical membrane in the mouse and the data are consistent with the reported electrogenicity of slc26a6. However, the role of SLC26A6 in human pancreatic HCO3^- secretion is less clear because human ducts are capable of secreting much higher concentrations of HCO3^-. The role of SLC26A6 must now be evaluated in a species such as the guinea pig which, like the human, is capable of secreting HCO3^- at a concentration of -140 mmol/L. From existing guinea pig data we calculate that a 1 Cl^--2HCO3^- exchanger such as slc26a6 would be unable to secrete HCO3^- against such a steep gradient. On the other hand, the HCO3^- conductance of CFTR could theoretically support secretion of HCO3^- to a much higher concentrations. CFTR may therefore play a more important role than SLC26A6 in HCO3^- secretion by the guinea pig and human pancreas.