title: The electroneutral Na⁺:HCO₃⁻ cotransporter NBCn1 is a major pHi regulator in murine duodenum.
abstract: Duodenocyte pHi control and HCO3 − secretion protects the proximal duodenum against damage by gastric acid. The molecular details of duodenocyte pH control are not well understood. A selective duodenal expression (within the upper GI tract) has been reported for the electroneutral Na+:HCO3 − cotransporter NBCn1 (Slc4a7). We aimed to determine the role of NBCn1 and NBCe2 in duodenocyte intracellular pH regulation as well as basal and agonist-stimulated duodenal bicarbonate secretion (JHCO3 −), exploiting mouse models of genetic slc4a7 and slc4a5 disruption. Basal and forskolin (FSK)-stimulated JHCO3 − was measured by single-pass perfusion in the duodenum of slc4a7−/− and slc4a7+/+ as well as slc4a5−/− and slc4a5+/+ mice in vivo, and by pH-stat titration in isolated duodenal mucosa in vitro. Duodenocyte HCO3 − uptake rates were fluorometrically assessed after acidification of intact villi and of isolated duodenocytes. Slc4a7−/− mice displayed significantly lower basal and FSK-stimulated duodenal HCO3 − secretion than slc4a7+/+ littermates in vivo. FSK-stimulated HCO3 − secretion was significantly reduced in slc4a7−/− isolated duodenal mucosa. Na+- and HCO3 −-dependent base uptake rates were significantly decreased in slc4a7−/− compared with slc4a7+/+ villus duodenocytes when measured in intact villi. Carbonic anhydrase (CA)-mediated CO2 hydration played no apparent role as a HCO3 − supply mechanism for basal or FSK-stimulated secretion in the slc4a7+/+ duodenum, but was an important alternative HCO3 − supply mechanism in the slc4a7−/− duodenum. NBCe2 (Slc4a5) displayed markedly lower duodenal mRNA expression levels, and its disruption did not interfere with duodenal HCO3 − secretion. The electroneutral Na+:HCO3 − cotransporter NBCn1 (slc4a7) is a major duodenal HCO3 − importer that supplies HCO3 − during basal and FSK-stimulated HCO3 − secretion.
authors.affiliation: Department of Gastroenterology, Hannover Medical School, Carl-Neuberg-Straße 1, Hannover, D-30625, Germany.
authors.forename: Mingmin
authors.initials: M
authors.lastname: Chen
authors.forename: Jeppe
authors.initials: J
authors.lastname: Praetorius
authors.forename: Wen
authors.initials: W
authors.lastname: Zheng
authors.forename: Fang
authors.initials: F
authors.lastname: Xiao
authors.forename: Brigitte
authors.initials: B
authors.lastname: Riederer
authors.forename: Anurag Kumar
authors.initials: AK
authors.lastname: Singh
authors.forename: Nicole
authors.initials: N
authors.lastname: Stieger
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Gary E
authors.initials: GE
authors.lastname: Shull
authors.forename: Christian
authors.initials: C
authors.lastname: Aalkjaer
authors.forename: Ursula
authors.initials: U
authors.lastname: Seidler
mesh_terms: D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D002245:Carbon Dioxide / Q000378:metabolism; D002256:Carbonic Anhydrases / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D004386:Duodenum / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis; D012964:Sodium / Q000378:metabolism; D027982:Sodium-Bicarbonate Symporters / Q000235:genetics / Q000378:metabolism*
chemical_list: D001639:Bicarbonates; D012333:RNA, Messenger; C530862:SLC4A5 protein, mouse; C498904:Slc4a7 protein, mouse; D027982:Sodium-Bicarbonate Symporters; D002245:Carbon Dioxide; D005576:Colforsin; D012964:Sodium; D002256:Carbonic Anhydrases