title: Molecular transport machinery involved in orchestrating luminal acid-induced duodenal bicarbonate secretion in vivo.
abstract: The duodenal villus brush border membrane expresses several ion transporters and/or channels, including the solute carrier 26 anion transporters Slc26a3 (DRA) and Slc26a6 (PAT-1), the Na(+)/H(+) exchanger isoform 3 (NHE3), as well as the anion channels cystic fibrosis transmembrane conductance regulator (CFTR) and Slc26a9. Using genetically engineered mouse models lacking Scl26a3, Slc26a6, Slc26a9 or Slc9a3 (NHE3), the study was carried out to assess the role of these transporters in mediating the protective duodenal bicarbonate secretory response (DBS-R) to luminal acid; and to compare it to their role in DBS-R elicited by the adenylyl cyclase agonist forskolin. While basal DBS was reduced in the absence of any of the three Slc26 isoforms, the DBS-R to forskolin was not altered. In contrast, the DBS-R to a 5 min exposure to luminal acid (pH 2.5) was strongly reduced in the absence of Slc26a3 or Slc26a9, but not Slc26a6. CFTR inhibitor [CFTR(Inh)-172] reduced the first phase of the acid-induced DBS-R, while NHE3 inhibition (or knockout) abolished the sustained phase of the DBS-R. Luminal acid exposure resulted in the activation of multiple intracellular signalling pathways, including SPAK, AKT and p38 phosphorylation. It induced a biphasic trafficking of NHE3, first rapidly into the brush border membrane, followed by endocytosis in the later stage. We conclude that the long-lasting DBS-R to luminal acid exposure activates multiple duodenocyte signalling pathways and involves changes in trafficking and/or activity of CFTR, Slc26 isoforms Slc26a3 and Slc26a9, and NHE3.
authors.affiliation: Prof. Dr. U. Seidler: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, D-30625 Germany. Seidler.Ursula@mh-hannover.de.
authors.forename: Anurag Kumar
authors.initials: AK
authors.lastname: Singh
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Liu
authors.forename: Brigitte
authors.initials: B
authors.lastname: Riederer
authors.forename: Regina
authors.initials: R
authors.lastname: Engelhardt
authors.forename: Basant Kumar
authors.initials: BK
authors.lastname: Thakur
authors.forename: Manoocher
authors.initials: M
authors.lastname: Soleimani
authors.forename: Ursula
authors.initials: U
authors.lastname: Seidler
mesh_terms: D000818:Animals; D017920:Antiporters / Q000235:genetics / Q000378:metabolism*; D001565:Benzoates / Q000494:pharmacology; D001639:Bicarbonates / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000378:metabolism; D004386:Duodenum / Q000378:metabolism*; D004705:Endocytosis; D006863:Hydrogen-Ion Concentration; D007413:Intestinal Mucosa / Q000378:metabolism; D017136:Ion Transport; D020935:MAP Kinase Signaling System; D051379:Mice; D010766:Phosphorylation; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000076988:Sulfate Transporters; D053778:Thiazolidines / Q000494:pharmacology
chemical_list: C482900:3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone; D017920:Antiporters; D001565:Benzoates; D001639:Bicarbonates; C489860:Slc26a3 protein, mouse; C466900:Slc26a6 protein, mouse; C533708:Slc26a9 protein, mouse; C000613386:Slc9a3 protein, mouse; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D000076988:Sulfate Transporters; D053778:Thiazolidines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin
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