Characterization of CFTR High Expresser cells in the intestine

Jakab, Robert L.; Collaco, Anne; Ameen, Nadia

doi:10.1152/ajpgi.00094.2013

Cited by 39 publications

(38 citation statements)

References 58 publications

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“…If CFTR is indeed functionally active in these cells, they could contribute significantly to the secretory diarrhea in MVID. Morphological studies of villus CHE cells support a secretory function as they express higher levels of basolateral NKCC1, lack apical NHE3, but possess very high levels of CFTR that undergo robust trafficking into the BBM upon cyclic nucleotide stimulation (3,26).…”

Section: Discussionmentioning

confidence: 90%

Identification of intestinal ion transport defects in microvillus inclusion disease

Kravtsov

Ahsan

Kumari

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Loss of function mutations in the actin motor myosin Vb (Myo5b) lead to microvillus inclusion disease (MVID) and death in newborns and children. MVID results in secretory diarrhea, brush border (BB) defects, villus atrophy, and microvillus inclusions (MVIs) in enterocytes. How loss of Myo5b results in increased stool loss of chloride (Cl Ϫ ) and sodium (Na ϩ ) is unknown. The present study used Myo5b loss-of-function human MVID intestine, polarized intestinal cell models of secretory crypt (T84) and villus resembling (CaCo2BBe, C2BBe) enterocytes lacking Myo5b in conjunction with immunofluorescence confocal stimulated emission depletion (gSTED) imaging, immunohistochemical staining, transmission electron microscopy, shRNA silencing, immunoblots, and electrophysiological approaches to examine the distribution, expression, and function of the major BB ion transporters NHE3 (Na ϩ ), CFTR (Cl Ϫ ), and SLC26A3 (DRA) (Cl Ϫ /HCO3 Ϫ ) that control intestinal fluid transport. We hypothesized that enterocyte maturation defects lead villus atrophy with immature secretory cryptlike enterocytes in the MVID epithelium. We investigated the role of Myo5b in enterocyte maturation. NHE3 and DRA localization and function were markedly reduced on the BB membrane of human MVID enterocytes and Myo5bKD C2BBe cells, while CFTR localization was preserved. Forskolin-stimulated CFTR ion transport in Myo5bKD T84 cells resembled that of control. Loss of Myo5b led to YAP1 nuclear retention, retarded enterocyte maturation, and a cryptlike phenotype. We conclude that preservation of functional CFTR in immature enterocytes, reduced functional expression of NHE3, and DRA contribute to Cl Ϫ and Na ϩ stool loss in MVID diarrhea.CFTR; brush border; MVI; Myo5b; NHE3; MVID MICROVILLUS INCLUSION DISEASE (MVID) is a rare but life-threatening disease that affects newborns and children and leads to rapid death from severe secretory diarrhea. MVID clusters in the Middle East and Navajo Indian populations in the US and is associated with consanguinity (41,42,47,51,61). Stool volumes are greater than 125 ml·kg Ϫ1 ·day Ϫ1 with elevated levels of chloride (Cl Ϫ ) and sodium (Na

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Section: Discussionmentioning

confidence: 90%

Identification of intestinal ion transport defects in microvillus inclusion disease

Kravtsov

Ahsan

Kumari

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Indeed, in K18 Ϫ/Ϫ (8) and K8 Ϫ/Ϫ (2) small intestine villi (but not crypts), CFTR surface expression was reduced. However, in K8 Ϫ/Ϫ mice, colonic crypt CFTR had normal apical levels and localization pattern (2), suggesting a cell type-specific regulation of CFTR by intermediate filaments (16). K8 ϩ/Ϫ mice, which have a significant and intermediate lower Cl…”

Section: Discussionmentioning

confidence: 99%

Keratin 8 knockdown leads to loss of the chloride transporter DRA in the colon

Asghar

Priyamvada

Nyström

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Asghar MN, Priyamvada S, Nyström JH, Anbazhagan AN, Dudeja PK, Toivola DM. Keratin 8 knockdown leads to loss of the chloride transporter DRA in the colon. Am J Physiol Gastrointest Liver Physiol 310: G1147-G1154, 2016. First published April 28, 2016 doi:10.1152 doi:10. /ajpgi.00354.2015 are intermediate filament proteins important in protection from stress. The roles of keratins in the intestine are not clear, but K8 knockout (K8 Ϫ/Ϫ ) mice develop a Th2-type colonic inflammation, epithelial hyperproliferation, and mild diarrhea caused by a keratin level-dependent decrease in short-circuit current and net sodium and chloride absorption in the distal colon. The lack of K8 leads to mistargeting or altered levels of membrane proteins in colonocytes; however, the main transporter responsible for the keratin-related ion transport defect is unknown. We here analyzed protein and mRNA levels of candidate ion transporters CFTR, PAT-1, NHE-3, and DRA in ileum, cecum, and proximal and distal colon. Although no differences were observed for CFTR, PAT-1, or NHE-3, DRA mRNA levels were decreased by three-to fourfold and DRA protein was almost entirely lost in K8 Ϫ/Ϫ cecum and proximal and distal colon compared with K8 ϩ/ϩ , whereas the levels in ileum were normal. In K8 ϩ/Ϫ mice, DRA mRNA levels were unaltered, while decreased DRA protein levels were detected in the proximal colon. Immunofluorescence staining confirmed the loss of DRA in K8 Ϫ/Ϫ distal colon, while K8 ϩ/Ϫ displayed a similar but more patchy apical DRA distribution compared with K8 ϩ/ϩ . DRA was similarly decreased when K8 was knocked down in Caco-2 cells, confirming that K8 levels modulate DRA levels in an inflammationindependent manner. Taken together, the loss of DRA in the K8

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“…In the small intestine CFTR expression decreases from duodenum to ileum with strongest expression in the crypts[112]. In addition, functional CFTR is found on the brush border of villus cells and rare CFTR-high expressing cells throughout the small intestine[113]. In the colon CFTR is expressed in a proximal to distal gradient with highest concentration in the proximal region and cecum.…”

Section: Chloride Channelsmentioning

confidence: 99%

Role of ion channels in gastrointestinal cancer

Anderson¹,

Cormier²,

Scott³

2019

WJG

136

103

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In their seminal papers Hanahan and Weinberg described oncogenic processes a normal cell undergoes to be transformed into a cancer cell. The functions of ion channels in the gastrointestinal (GI) tract influence a variety of cellular processes, many of which overlap with these hallmarks of cancer. In this review we focus on the roles of the calcium (Ca2+), sodium (Na+), potassium (K+), chloride (Cl-) and zinc (Zn2+) transporters in GI cancer, with a special emphasis on the roles of the KCNQ1 K+ channel and CFTR Cl- channel in colorectal cancer (CRC). Ca2+ is a ubiquitous second messenger, serving as a signaling molecule for a variety of cellular processes such as control of the cell cycle, apoptosis, and migration. Various members of the TRP superfamily, including TRPM8, TRPM7, TRPM6 and TRPM2, have been implicated in GI cancers, especially through overexpression in pancreatic adenocarcinomas and down-regulation in colon cancer. Voltage-gated sodium channels (VGSCs) are classically associated with the initiation and conduction of action potentials in electrically excitable cells such as neurons and muscle cells. The VGSC NaV1.5 is abundantly expressed in human colorectal CRC cell lines as well as being highly expressed in primary CRC samples. Studies have demonstrated that conductance through NaV1.5 contributes significantly to CRC cell invasiveness and cancer progression. Zn2+ transporters of the ZIP/SLC39A and ZnT/SLC30A families are dysregulated in all major GI organ cancers, in particular, ZIP4 up-regulation in pancreatic cancer (PC). More than 70 K+ channel genes, clustered in four families, are found expressed in the GI tract, where they regulate a range of cellular processes, including gastrin secretion in the stomach and anion secretion and fluid balance in the intestinal tract. Several distinct types of K+ channels are found dysregulated in the GI tract. Notable are hERG1 upregulation in PC, gastric cancer (GC) and CRC, leading to enhanced cancer angiogenesis and invasion, and KCNQ1 down-regulation in CRC, where KCNQ1 expression is associated with enhanced disease-free survival in stage II, III, and IV disease. Cl- channels are critical for a range of cellular and tissue processes in the GI tract, especially fluid balance in the colon. Most notable is CFTR, whose deficiency leads to mucus blockage, microbial dysbiosis and inflammation in the intestinal tract. CFTR is a tumor suppressor in several GI cancers. Cystic fibrosis patients are at a significant risk for CRC and low levels of CFTR expression are associated with poor overall disease-free survival in sporadic CRC. Two other classes of chloride channels that are dysregulated in GI cancers are the chloride intracellular channels (CLIC1, 3 & 4) and the chloride channel accessory proteins (CLCA1,2,4). CLIC1 & 4 are upregulated in PC, GC, gallbladder cancer, and CRC, while the CLCA proteins have been reported to be down-regulated in CRC. In summary, it is clear, from the diverse influences of ion channels, that their aberrant expression and/or activity c...

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Characterization of CFTR High Expresser cells in the intestine

Cited by 39 publications

References 58 publications

Identification of intestinal ion transport defects in microvillus inclusion disease

Identification of intestinal ion transport defects in microvillus inclusion disease

Keratin 8 knockdown leads to loss of the chloride transporter DRA in the colon

Role of ion channels in gastrointestinal cancer

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