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

Abstract

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 ∼140 mM HCO3− or more, mouse and rat ducts secrete ∼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 36Cl− 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.

The Divergence, Actions, Roles, and Relatives of Sodium-Coupled Bicarbonate Transporters

“…2 For the purposes of this review, we depict Slc26a3, -4, -6, -7, and -9 as electroneutral Cl-HCO 3 exchangers; in fact, the molecular action of these Slc26 transporters is controversial. Slc26a3 has been described as being capable of electroneutral Cl-HCO 3 exchange by some (26,908) but electrogenic 2Cl-HCO 3 exchange by others (499,871). Slc26a4 is capable of electroneutral Cl-HCO 3 exchange (872), a description that is uncontested.…”

Overlapping expression of anion exchangers in the cochlea of a non-human primate suggests functional compensation

“…This transporter exchanges Cl − , SO 4 2− , HCO 3 − and oxalate (Stewart et al, 2011). Disease-related mutations or mouse KO models of this gene have not been reported.…”

Divergent CFTR orthologs respond differently to the channel inhibitors CFTRinh-172, glibenclamide, and GlyH-101

“…Glibenclamide inhibits other ATP-binding cassette (ABC) transporters including the sulfonylurea receptor and P-glycoprotein (4) and calcium-activated Cl Ϫ channels in mammalian cardiac myocytes (64). GlyH-101 inhibits other anion channels and transporters such as TMEM16A (10) and the SLC26 anion exchangers SLC26a3, -a6, a9, and -a11 (3,56). CFTR inh -172 inhibits sodium transport in sweat glands (62).…”