SLC26 anion exchangers of guinea pig pancreatic duct: molecular cloning and functional characterization

Stewart AK, Shmukler BE, Vandorpe DH, Reimold F, Heneghan JF, Nakakuki M, Akhavein A, Ko S, Ishiguro H, Alper SL. SLC26 anion exchangers of guinea pig pancreatic duct: molecular cloning and functional characterization. Am J Physiol Cell Physiol 301: C289-C303, 2011. First published May 18, 2011; doi: 10.1152/ajpcell.00089.2011.-The secretin-stimulated human pancreatic duct secretes HCO3--rich fluid essential for normal digestion. Optimal stimulation of pancreatic HCO3- secretion likely requires coupled activities of the cystic fibrosis transmembrane regulator (CFTR) anion channel and apical SLC26 Cl-/HCO3- exchangers. However, whereas stimulated human and guinea pig pancreatic ducts secrete similar to 140 mM HCO3- or more, mouse and rat ducts secrete similar to 40-70 mM HCO3-. Moreover, the axial distribution and physiological roles of SLC26 anion exchangers in pancreatic duct secretory processes remain controversial and may vary among mammalian species. Thus the property of high HCO3- secretion shared by human and guinea pig pancreatic ducts prompted us to clone from guinea pig pancreatic duct cDNAs encoding Slc26a3, Slc26a6, and Slc26a11 polypeptides. We then functionally characterized these anion transporters in Xenopus oocytes and human embryonic kidney (HEK) 293 cells. In Xenopus oocytes, gpSlc26a3 mediated only Cl-/Cl- exchange and electroneutral Cl-/HCO3- exchange. gpSlc26a6 in Xenopus oocytes mediated Cl-/Cl- exchange and bidirectional exchange of Cl- for oxalate and sulfate, but Cl-/HCO3- exchange was detected only in HEK 293 cells. gpSlc26a11 in Xenopus oocytes exhibited pH-dependent Cl-, oxalate, and sulfate transport but no detectable Cl- /HCO3- exchange. The three gpSlc26 anion transporters exhibited distinct pharmacological profiles of Cl-36(-) influx, including partial sensitivity to CFTR inhibitors Inh-172 and GlyH101, but only Slc26a11 was inhibited by PPQ-102. This first molecular and functional assessment of recombinant SLC26 anion transporters from guinea pig pancreatic duct enhances our understanding of pancreatic HCO3- secretion in species that share a high HCO3- secretory output.