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1 Departments of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
2 Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, United States
3 Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
* To whom correspondence should be addressed. E-mail: mhm{at}uc.edu.
The mechanism of apical Na-dependent H+ extrusion in colonic crypts is controversial. Using confocal microscopy of living mouse distal colon loaded with BCECF or SNARF-5F (fluorescent pH sensors), measurements of intracellular pH (pHi) in epithelial cells at either the crypt base or the colonic surface are reported. Following cellular acidification, addition of luminal Na+ stimulated similar rates of pHi recovery in cells at the base of distal colonic crypts of wild-type or NHE2-null mice. In wild-type crypts, 20 µM HOE694 (NHE2 inhibitor) blocked 68-75% of pHi recovery rate, whereas NHE2-null crypts were insensitive to HOE694, NHE3-specific inhibitor (20 µM) S-1611, or a bicarbonate transport inhibitor (1 mM) SITS. A general NHE inhibitor, (20 µM) EIPA, inhibited pHi recovery in NHE2-null mice (46%), but less strongly than in wild-type (74%), suggesting both EIPA-sensitive and -insensitive compensatory mechanisms. Transepithelial Na+ leakage followed by activation of basolateral NHE1 could confound outcomes; however, rates of Na+-dependent pHi recovery were independent of transepithelial leakiness to Lucifer Yellow and were unchanged in NHE1-null mice. NHE2 was immunolocalized on apical membranes of wild-type crypts but not NHE2-null tissue. NHE3-immunoreactivity was near the colonic surface but not at the crypt base in NHE2-null mice. Colonic surface cells from wild-type mice demonstrate S1611- and HOE694-sensitive pHi recovery in response to luminal sodium, confirming a functional role for both NHE3 and NHE2 at this site. We conclude that constitutive absence of NHE2 results in a compensatory increase in a Na+-dependent, EIPA-sensitive acid extruder distinct from NHE1, NHE3 or SITS-sensitive transporters.
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