Na+-dependent transporters mediate HCO3– salvage across the luminal membrane of the main pancreatic duct

Lee, Min Goo; Ahn, Wooin; Choi, Joo Young; Luo, Xiang; Seo, Jeong Taeg; Schultheis, Patrick J.; Shull, Gary E.; Kim, Kyung Hwan; Muallem, Shmuel

doi:10.1172/jci9207

Cited by 70 publications

(82 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Immunostaining of frozen sections was performed as previously reported (8). Briefly, the sections were fixed and permeabilized by incubation with cold methanol for 10 min at Ϫ20°C.…”

Section: Methodsmentioning

confidence: 99%

“…The mice were maintained on a standard diet, and genotyping was carried out during days 7-14 postpartum, as described (22). The procedure for preparation and perfusion of the main pancreatic duct was identical to that described previously (8). Briefly, the mice were anesthetized, the abdomen was opened, and the duct lumen was cannulated using a modified 31-gauge needle.…”

Section: Methodsmentioning

confidence: 99%

“…We previously showed that 50% of the luminal Na ϩ -dependent pH i increase is mediated by NHE3 and about 50% by a novel, Na ϩ -dependent, and amiloride-sensitive mechanism different from any known NHE isoform (8). The Na ϩ -dependent pH i increase was measured in perfused ducts from WT and ⌬F mice.…”

Section: Biochemical and Functional Association Of Cftr With Nhe3 Inmentioning

confidence: 99%

“…Importantly, aberrant HCO 3 Ϫ transport in cells expressing CFTR mutants that retain Cl Ϫ channel activity correlates with the pancreatic status of the CF phenotype (7). Another HCO 3 Ϫ -transporting mechanism in tissues that express CFTR is HCO 3 Ϫ -absorbing processes that may function as HCO 3 Ϫ salvage mechanisms in the resting state (8). In the pancreatic duct (8) and the kidney proximal tubule (9), 50% of HCO 3 Ϫ absorption is mediated by the Na ϩ /H ϩ exchanger isoform 3 (NHE3) and 50% by a novel, yet unidentified, Na ϩ -dependent mechanism.…”

Section: Patients (1) Cf Is Caused By Mutations In the Cystic Fibrosmentioning

confidence: 99%

“…Another HCO 3 Ϫ -transporting mechanism in tissues that express CFTR is HCO 3 Ϫ -absorbing processes that may function as HCO 3 Ϫ salvage mechanisms in the resting state (8). In the pancreatic duct (8) and the kidney proximal tubule (9), 50% of HCO 3 Ϫ absorption is mediated by the Na ϩ /H ϩ exchanger isoform 3 (NHE3) and 50% by a novel, yet unidentified, Na ϩ -dependent mechanism. Hence, HCO 3 Ϫ homeostasis in secretory epithelia is accomplished by both HCO 3 Ϫ -absorbing (resting state) and HCO 3 Ϫ -secretory (stimulated state) mechanisms.…”

Section: Patients (1) Cf Is Caused By Mutations In the Cystic Fibrosmentioning

confidence: 99%

See 4 more Smart Citations

Regulatory Interaction between the Cystic Fibrosis Transmembrane Conductance Regulator and HCO 3− Salvage Mechanisms in Model Systems and the Mouse Pancreatic Duct

Ahn

Kim

Lee

et al. 2001

Journal of Biological Chemistry

Self Cite

105

114

View full text Add to dashboard Cite

The pancreatic duct expresses cystic fibrosis transmembrane conductance regulator (CFTR) and HCO 3 ؊ secretory and salvage mechanisms in the luminal membrane. Although CFTR plays a prominent role in HCO 3 ؊ secretion, the role of CFTR in HCO 3 ؊ salvage is not known. In the present work, we used molecular, biochemical, and functional approaches to study the regulatory interaction between CFTR and the HCO 3 ؊ salvage mechanism Na ؉ /H ؉ exchanger isoform 3 (NHE3) in heterologous expression systems and in the native pancreatic duct. We found that CFTR regulates NHE3 activity by both acute and chronic mechanisms. In the pancreatic duct, CFTR increases expression of NHE3 in the luminal membrane. Thus, luminal expression of NHE3 was reduced by 53% in ducts of homozygote ⌬F508 mice. Accordingly, luminal Na ؉ -dependent and HOE694-sensitive recovery from an acid load was reduced by 60% in ducts of ⌬F508 mice. CFTR and NHE3 were coimmunoprecipitated from PS120 cells expressing both proteins and the pancreatic duct of wild type mice but not from PS120 cells lacking CFTR or the pancreas of ⌬F508 mice. The interaction between CFTR and NHE3 required the COOH-terminal PDZ binding motif of CFTR, and mutant CFTR proteins lacking the C terminus were not co-immunoprecipitated with NHE3. Furthermore, when expressed in PS120 cells, wild type CFTR, but not CFTR mutants lacking the C-terminal PDZ binding motif, augmented cAMP-dependent inhibition of NHE3 activity by 31%. These findings reveal that CFTR controls overall HCO 3 ؊ homeostasis by regulating both pancreatic ductal HCO 3 ؊ secretory and salvage mechanisms.Fluid secretion and the control of the ionic composition of biological fluids are essential for the function of many secretory epithelia, including the respiratory, digestive, and reproductive systems. HCO 3 Ϫ is an important constituent of secreted fluids by virtue of its function as the biological pH buffer and its effect on the solubility of proteins and ions in biological fluids. Accordingly, the mechanisms underlying HCO 3 Ϫ homeostasis at rest and during stimulation have attracted much attention in recent years. The importance of HCO 3 Ϫ homeostasis is evident from the marked reduction in Cl Ϫ -and HCO 3 Ϫ

show abstract

“…Immunostaining of frozen sections was performed as previously reported (8). Briefly, the sections were fixed and permeabilized by incubation with cold methanol for 10 min at Ϫ20°C.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Biochemical and Functional Association Of Cftr With Nhe3 Inmentioning

confidence: 99%