Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Am J Physiol Cell Physiol
2018 Aug 01;3152:C258-C276. doi: 10.1152/ajpcell.00130.2018.
Show Gene links
Show Anatomy links
Mistargeting of a truncated Na-K-2Cl cotransporter in epithelial cells.
Koumangoye R
,
Omer S
,
Delpire E
.
???displayArticle.abstract???
We recently reported the case of a young patient with multisystem failure carrying a de novo mutation in SLC12A2, the gene encoding the Na-K-2Cl cotransporter-1 (NKCC1). Heterologous expression studies in nonepithelial cells failed to demonstrate dominant-negative effects. In this study, we examined expression of the mutant cotransporter in epithelial cells. Using Madin-Darby canine kidney (MDCK) cells grown on glass coverslips, permeabilized support, and Matrigel, we show that the fluorescently tagged mutant cotransporter is expressed in cytoplasm and at the apical membrane and affects epithelium integrity. Expression of the mutant transporter at the apical membrane also results in the mislocalization of some of the wild-type transporter to the apical membrane. This mistargeting is specific to NKCC1 as the Na+-K+-ATPase remains localized on the basolateral membrane. To assess transporter localization in vivo, we created a mouse model using CRISPR/cas9 that reproduces the 11 bp deletion in exon 22 of Slc12a2. Although the mice do not display an overt phenotype, we show that the colon and salivary gland expresses wild-type NKCC1 abundantly at the apical pole, confirming the data obtained in cultured epithelial cells. Enough cotransporter must remain, however, on the basolateral membrane to participate in saliva secretion, as no significant decrease in saliva production was observed in the mutant mice.
Best,
Salivary secretion assay for drug efficacy for cystic fibrosis in mice.
2005, Pubmed
Best,
Salivary secretion assay for drug efficacy for cystic fibrosis in mice.
2005,
Pubmed
Carmosino,
Exon loss accounts for differential sorting of Na-K-Cl cotransporters in polarized epithelial cells.
2008,
Pubmed
Damkier,
Cerebrospinal fluid secretion by the choroid plexus.
2013,
Pubmed
Debnath,
Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures.
2003,
Pubmed
Delpire,
Deafness and imbalance associated with inactivation of the secretory Na-K-2Cl co-transporter.
1999,
Pubmed
Delpire,
Housing and husbandry of Xenopus laevis affect the quality of oocytes for heterologous expression studies.
2011,
Pubmed
,
Xenbase
Delpire,
Molecular cloning and chromosome localization of a putative basolateral Na(+)-K(+)-2Cl- cotransporter from mouse inner medullary collecting duct (mIMCD-3) cells.
1994,
Pubmed
Delpire,
A patient with multisystem dysfunction carries a truncation mutation in human SLC12A2, the gene encoding the Na-K-2Cl cotransporter, NKCC1.
2016,
Pubmed
Dharmsathaphorn,
Vasoactive intestinal polypeptide-induced chloride secretion by a colonic epithelial cell line. Direct participation of a basolaterally localized Na+,K+,Cl- cotransport system.
1985,
Pubmed
Engelberg,
MDCK cystogenesis driven by cell stabilization within computational analogues.
2011,
Pubmed
Evans,
Severe impairment of salivation in Na+/K+/2Cl- cotransporter (NKCC1)-deficient mice.
2000,
Pubmed
Flagella,
Mice lacking the basolateral Na-K-2Cl cotransporter have impaired epithelial chloride secretion and are profoundly deaf.
1999,
Pubmed
Frizzell,
Physiology of epithelial chloride and fluid secretion.
2012,
Pubmed
Gabriel,
Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model.
1994,
Pubmed
Gagnon,
Volume sensitivity of cation-Cl- cotransporters is modulated by the interaction of two kinases: Ste20-related proline-alanine-rich kinase and WNK4.
2006,
Pubmed
,
Xenbase
Gagnon,
Physiology of SLC12 transporters: lessons from inherited human genetic mutations and genetically engineered mouse knockouts.
2013,
Pubmed
Gong,
Biochemical and immunological mechanisms by which sickle cell trait protects against malaria.
2013,
Pubmed
Hartmann,
Opposite effect of membrane raft perturbation on transport activity of KCC2 and NKCC1.
2009,
Pubmed
Heintze,
Sodium-dependent chloride secretion across rabbit descending colon.
1983,
Pubmed
Hoekstra,
The subapical compartment: a traffic center in membrane polarity development.
2004,
Pubmed
Howard,
The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum.
2002,
Pubmed
,
Xenbase
Josefson,
CF gene may protect against typhoid fever.
1998,
Pubmed
Kaplan,
Apical localization of the Na-K-Cl cotransporter, rBSC1, on rat thick ascending limbs.
1996,
Pubmed
Kaplan,
Expression of the mouse Na-K-2Cl cotransporter, mBSC2, in the terminal inner medullary collecting duct, the glomerular and extraglomerular mesangium, and the glomerular afferent arteriole.
1996,
Pubmed
Karimy,
Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus.
2017,
Pubmed
Kidokoro,
Na(+)-K(+)-2Cl(-) cotransporter-mediated fluid secretion increases under hypotonic osmolarity in the mouse submandibular salivary gland.
2014,
Pubmed
Lytle,
Coordinate modulation of Na-K-2Cl cotransport and K-Cl cotransport by cell volume and chloride.
2002,
Pubmed
Martín-Belmonte,
Cell-polarity dynamics controls the mechanism of lumen formation in epithelial morphogenesis.
2008,
Pubmed
McRoberts,
Characterization of low potassium-resistant mutants of the Madin-Darby canine kidney cell line with defects in NaCl/KCl symport.
1983,
Pubmed
Moore-Hoon,
The structural unit of the secretory Na+-K+-2Cl- cotransporter (NKCC1) is a homodimer.
2000,
Pubmed
Murek,
Evidence for intestinal chloride secretion.
2010,
Pubmed
Murthy,
WNK signalling pathways in blood pressure regulation.
2017,
Pubmed
Nezu,
A conserved hydrophobic tetrad near the C terminus of the secretory Na+-K+-2Cl- cotransporter (NKCC1) is required for its correct intracellular processing.
2009,
Pubmed
Pace,
Failure of spermatogenesis in mouse lines deficient in the Na(+)-K(+)-2Cl(-) cotransporter.
2000,
Pubmed
Parvin,
Regions in the cytosolic C-terminus of the secretory Na(+)-K(+)-2Cl(-) cotransporter NKCC1 are required for its homodimerization.
2007,
Pubmed
Patterson,
A quantitative analysis of electrolyte exchange in the salivary duct.
2012,
Pubmed
Payne,
Endogenous and exogenous Na-K-Cl cotransporter expression in a low K-resistant mutant MDCK cell line.
2001,
Pubmed
Ponce-Coria,
A novel Ste20-related proline/alanine-rich kinase (SPAK)-independent pathway involving calcium-binding protein 39 (Cab39) and serine threonine kinase with no lysine member 4 (WNK4) in the activation of Na-K-Cl cotransporters.
2014,
Pubmed
Randall,
Partial cloning and characterization of Slc12a2: the gene encoding the secretory Na+-K+-2Cl- cotransporter.
1997,
Pubmed
Saint-Criq,
Role of CFTR in epithelial physiology.
2017,
Pubmed
Simard,
Self-interacting domains in the C terminus of a cation-Cl- cotransporter described for the first time.
2004,
Pubmed
Stoops,
Trafficking to the apical and basolateral membranes in polarized epithelial cells.
2014,
Pubmed
Thwaites,
H+-coupled nutrient, micronutrient and drug transporters in the mammalian small intestine.
2007,
Pubmed
Verouti,
Regulation of blood pressure and renal function by NCC and ENaC: lessons from genetically engineered mice.
2015,
Pubmed
Warmuth,
X-ray structure of the C-terminal domain of a prokaryotic cation-chloride cotransporter.
2009,
Pubmed
Welling,
Multigene kinase network, kidney transport, and salt in essential hypertension.
2010,
Pubmed
Wright,
Coupling between Na+, sugar, and water transport across the intestine.
2000,
Pubmed
Yamashita,
Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters.
2005,
Pubmed
Zdebik,
Potassium ion movement in the inner ear: insights from genetic disease and mouse models.
2009,
Pubmed
Zheng,
LGN regulates mitotic spindle orientation during epithelial morphogenesis.
2010,
Pubmed