TY - JOUR
T1 - Sulfate secretion and chloride absorption are mediated by the anion exchanger DRA (Slc26a3) in the mouse cecum
AU - Whittamore, Jonathan M.
AU - Freel, Robert W.
AU - Hatch, Marguerite
PY - 2013/7/15
Y1 - 2013/7/15
N2 - Inorganic sulfate (SO2-4) is essential for a multitude of physiological processes. The specific molecular pathway has been identified for uptake from the small intestine but is virtually unknown for the large bowel, although there is evidence for absorption involving Na+-independent anion exchange. A leading candidate is the apical chloride/bicarbonate (Cl-/HCO3-) exchanger DRA (down-regulated in adenoma; Slc26a3), primarily linked to the Cl- transporting defect in congenital chloride diarrhea. The present study set out to characterize transepithelial 35SO2-4 and 36Cl- fluxes across the isolated, short-circuited cecum from wild-type (WT) and knockout (KO) mice and subsequently to define the contribution of DRA. The cecum demonstrated simultaneous net SO2-4 secretion (-8.39 ± 0.88 nmol·cm-2·h-1) and Cl- absorption (10.85 ± 1.41 μmol·cm-2·h-1). In DRA-KO mice, SO2-4 secretion was reversed to net absorption via a 60% reduction in serosal to mucosal SO2-4 flux. Similarly, net Cl- absorption was abolished and replaced by secretion, indicating that DRA represents a major pathway for transcellular SO2-4 secretion and Cl- absorption. Further experiments including the application of DIDS (500 μM), bumetanide (100 μM), and substitutions of extracellular Cl- or HCO3-/CO2 helped to identify specific ion dependencies and driving forces and suggested that additional anion exchangers were operating at both apical and basolateral membranes supporting SO2-4 transport. In conclusion, DRA contributes to SO2-4 secretion via DIDS-sensitive HCO3-/SO2-4 exchange, in addition to being the principal DIDS-resistant Cl-/HCO3- exchanger. With DRA linked to the pathogenesis of other gastrointestinal diseases extending its functional characterization offers a more complete picture of its role in the intestine.
AB - Inorganic sulfate (SO2-4) is essential for a multitude of physiological processes. The specific molecular pathway has been identified for uptake from the small intestine but is virtually unknown for the large bowel, although there is evidence for absorption involving Na+-independent anion exchange. A leading candidate is the apical chloride/bicarbonate (Cl-/HCO3-) exchanger DRA (down-regulated in adenoma; Slc26a3), primarily linked to the Cl- transporting defect in congenital chloride diarrhea. The present study set out to characterize transepithelial 35SO2-4 and 36Cl- fluxes across the isolated, short-circuited cecum from wild-type (WT) and knockout (KO) mice and subsequently to define the contribution of DRA. The cecum demonstrated simultaneous net SO2-4 secretion (-8.39 ± 0.88 nmol·cm-2·h-1) and Cl- absorption (10.85 ± 1.41 μmol·cm-2·h-1). In DRA-KO mice, SO2-4 secretion was reversed to net absorption via a 60% reduction in serosal to mucosal SO2-4 flux. Similarly, net Cl- absorption was abolished and replaced by secretion, indicating that DRA represents a major pathway for transcellular SO2-4 secretion and Cl- absorption. Further experiments including the application of DIDS (500 μM), bumetanide (100 μM), and substitutions of extracellular Cl- or HCO3-/CO2 helped to identify specific ion dependencies and driving forces and suggested that additional anion exchangers were operating at both apical and basolateral membranes supporting SO2-4 transport. In conclusion, DRA contributes to SO2-4 secretion via DIDS-sensitive HCO3-/SO2-4 exchange, in addition to being the principal DIDS-resistant Cl-/HCO3- exchanger. With DRA linked to the pathogenesis of other gastrointestinal diseases extending its functional characterization offers a more complete picture of its role in the intestine.
KW - Epithelial ion transport
KW - Large intestine
KW - PAT1
KW - Slc26a6
UR - http://www.scopus.com/inward/record.url?scp=84880150933&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84880150933&partnerID=8YFLogxK
U2 - 10.1152/ajpgi.00084.2013
DO - 10.1152/ajpgi.00084.2013
M3 - Article
C2 - 23660504
AN - SCOPUS:84880150933
SN - 0193-1857
VL - 305
SP - G172-G184
JO - American Journal of Physiology - Gastrointestinal and Liver Physiology
JF - American Journal of Physiology - Gastrointestinal and Liver Physiology
IS - 2
ER -