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ORIGINAL ARTICLE

Evidence for the Existence of a Distinct SO₄^---OH^- Exchange Mechanism in the Human Proximal Colonic Apical Membrane Vesicles and Its Possible Role in Chloride Transport

Sangerta Tyagi^*, Reena J. Kavilaveettil, Waddah A. Alrefai^*, Shadwan Alsafwah, Krishnamurthy Ramaswamy^*, and Pradeep K. Dudeja^*,,1

^* Department of Medicine, University of Illinois, Chicago, Illinois 60612; and
Westside Veterans Affairs Medical Center, Chicago, Illinois 60612

Recent studies have demonstrated that mutations in human downregulated in adenoma gene (DRA) result in congenital chloride diarrhea (CLD), and that DRA may be involved in chloride transport across the intestinal apical domains. DRA is highly homologous to sulfate transporters, but not to any member of the anion exchanger gene family (AEs). Our previous studies have characterized the existence of a distinct Cl^--OH^- (HCO₃^-) exchanger, with minimal affinity for sulfate in the human colonic apical membrane vesicles (AMV). However, the mechanism(s) of sulfate movement across the colonocyte plasma membranes in the human colon is not well understood. Current studies were undertaken to elucidate sulfate transport pathways in AMVs of human proximal colon. Purified AMV and rapid filtration ³⁵SO₄^-- uptake techniques were used. Our results demonstrate the presence of a pH gradient-driven carrier-mediated SO₄^---OH^- exchange process in the human proximal colonic luminal membranes based on the following: a marked increase in the SO₄^-- uptake in the presence of an outwardly directed OH^- gradient; a significant inhibition of SO₄^-- uptake by the membrane anion transport inhibitor, DIDS; demonstration of saturation kinetics (K_m for SO₄^--: 0.80 ± 0.17 mM and Vmax 649 ± 74 pmol/mg protein/10 sec); competitive inhibition of SO₄^---OH^- exchange by oxalate; SO₄^-- uptake was insensitive to alterations in the membrane potential; and inwardly directed Na⁺ gradient under non-pH gradient conditions did not stimulate SO₄^-- uptake. SO₄^-- uptake was significantly inhibited by increasing concentrations of chloride (1–10 mM) in the incubation media with a K_i for Cl^- of 9.3 ± 1.4 mM. In contrast, OH^-/HCO₃^- gradient-driven ³⁶Cl^- uptake into these vesicles was unaffected by increasing concentrations of sulfate (10–50 mM). The above data indicate that two distinct transporters may be involved in SO₄^-- and Cl^- transport in the human intestinal apical membranes: an anion exchanger with high affinity for SO₄^-- and oxalate but low affinity for Cl^-, and a distinct Cl^--OH^- (HCO₃^-) exchanger with low affinity for SO₄^--.

Key Words: human intestine • congenital chloride diarrhea • downregulated in adenoma • sulfate transport

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