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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Regulation of intestinal Cl^–/HCO₃^– exchanger SLC26A3 by intracellular pH

¹Laboratory of Physiology and ²Laboratory of Nutritional Physiology, School of Nutritional Sciences, University of Shizuoka, Suruga-ku, Shizuoka, Japan

Submitted 15 December 2008 ; accepted in final form 23 March 2009

SLC26A3, a Cl^–/HCO₃^– exchanger, is highly expressed in intestinal epithelial cells, and its mutations cause congenital chloride diarrhea. This suggests that SLC26A3 plays a key role in NaCl absorption in the intestine. Electroneutral NaCl absorption in the intestine is mediated by functional coupling of the Na⁺/H⁺ exchanger and Cl^–/HCO₃^– exchanger. It is proposed that the coupling of these exchangers may occur as a result of indirect linkage by changes of intracellular pH (pH_i). We therefore investigated whether SLC26A3 is regulated by pH_i. We generated a hemagglutinin epitope-tagged human SLC26A3 construct and expressed it in Chinese hamster ovary cells. Transport activities were measured with a fluorescent chloride-sensitive dye dihydro-6-methoxy-N-ethylquinolinium iodide (diH-MEQ). pH_i was clamped at a range of values from 6.0 to 7.4. We monitored the transport activity of SLC26A3 by reverse mode of Cl^–/HCO₃^– and Cl^–/NO₃^– exchange. None of these exchange modes induced membrane potential changes. At constant external pH 7.4, Cl^–/HCO₃^– exchange was steeply inhibited with pH_i decrease between 7.3 and 6.8 as opposed to thermodynamic prediction. In contrast, however, Cl^–/NO₃^– exchange was essentially insensitive to pH_i within physiological ranges. We also characterized the pH_i dependency of COOH-terminal truncation mutants. Removal of the entire COOH-terminal resulted in decrease of the transport activity but did not noticeably affect pH_i sensitivity. These results suggest that Cl^–/HCO₃^– exchange mode of human SLC26A3 is controlled by a pH-sensitive intracellular modifier site, which is likely in the transmembrane domain. These observations raise the possibility that SLC26A3 activity may be regulated via Na⁺/H⁺ exchanger 3 (NHE3) through the alteration of pH_i under physiological conditions.

electroneutral NaCl absorption; downregulated in adenoma; dihydro-6-methoxy-N-ethylquinolinium iodide

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