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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

Ishiguro H, Steward M, Naruse S

名古屋大学医学研究生院人体营养学系,名古屋464-8601；日本

摘要

胰管细胞以至少6倍浓度差逆向分泌HCO_(3)~(-)（人体浓度约140mmol／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1Cl~(-)--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HCO_(3)~(-)，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140mmol／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1Cl~(-)--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。

关键词： 囊性纤维化跨膜电导调节体; SLC26; 胰管; HCO_(3)~(-)分泌

Cystic fibrosis transmembrane conductance regulator and SLC26 transporters in HCO_(3)~(-) secretion by pancreatic duct cells

Ishiguro H, Steward M, Naruse S

Departments of Human Nutrition, Nagoya University Graduate School of Medicine, Nagoya 464-8601；Japan

Abstract

Pancreatic duct cells secrete HCO_(3)~(-) ions into a HCO_(3)~(-)-rich luminal fluid （-140 mmol/L in human） against at least a 6-fold concentration gradient. Candidate mechanisms for HCO_(3)~(-) transport across the apical membrane include Cl~(-)-HCO_(3)~(-) exchange by an SLC26 anion transporter and diffusion via the HCO_(3)~(-) conductance of cystic fibrosis transmembrane conductance regulator （CFTR） Members of the SLC26 family are known to mediate Cl~(-)-HCO_(3)~(-) 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 1Cl~(-)-2HCO_(3)~(-) exchange and slc26a3 mediating 2Cl~(-)-1HCO_(3)~(-) exchange. Recent experiments using isolated pancreatic ducts from slc26a6~(-/-) mice suggest that slc26a6 mediates most of the Cl~(-)-dependent secretion of HCO_(3)~(-) 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 HCO_(3)~(-) secretion is less clear because human ducts are capable of secreting much higher concentrations of HCO_(3)~(-). The role of SLC26A6 must now be evaluated in a species such as the guinea pig which, like the human, is capable of secreting HCO_(3)~(-) at a concentration of -140 mmol/L. From existing guinea pig data we calculate that a 1Cl~(-)-2HCO_(3)~(-) exchanger such as slc26a6 would be unable to secrete HCO_(3)~(-) against such a steep gradient. On the other hand, the HCO_(3)~(-) conductance of CFTR could theoretically support secretion of HCO_(3)~(-) to a much higher concentrations. CFTR may therefore play a more important role than SLC26A6 in HCO_(3)~(-) secretion by the guinea pig and human pancreas.

Key words: cystic fibrosis transmembrane conductance regulator;SLC26;pancreatic duct;bicarbonate secretion

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引用本文：

Ishiguro H, Steward M, Naruse S. 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[J]. 生理学报 2007; 59 (4): 465-476.

Ishiguro H, Steward M, Naruse S. Cystic fibrosis transmembrane conductance regulator and SLC26 transporters in HCO_(3)~(-) secretion by pancreatic duct cells. Acta Physiol Sin 2007; 59 (4): 465-476 (in Chinese with English abstract).