Relationship of a Non-cystic Fibrosis Transmembrane Conductance Regulator-mediated Chloride Conductance to Organ-level Disease in Cftr(-/-) Mice

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1994 Jan 18

PMID 7507247

Citations 102

Authors

L L Clarke

B R Grubb

J R Yankaskas

C U Cotton

A Mckenzie

R C Boucher

Affiliations

Soon will be listed here.

Abstract

Although loss of cystic fibrosis transmembrane conductance regulator (CFTR)-mediated Cl- channel function is common to all epithelia in cystic fibrosis (CF) patients, the severity of disease varies in different organs. We hypothesized that differences in disease severity in CF relate to the expression of an "alternative" plasma membrane Cl- conductance. In CF mice [Cftr(-/-); mice homozygous for Ser-489 to Xaa mutation], which do not express cAMP CFTR-mediated Cl- secretion, we surveyed organs that exhibit a range of disease severity for a Ca(2+)-mediated apical membrane epithelial Cl- conductance. This alternative conductance (Cl-a) was detected in epithelia of organs from CF mice that exhibit a mild disease phenotype (airway, pancreas) but not in epithelia with a severe phenotype (small, large intestine). We conclude that (i) there is an intracellular Ca(2+)-regulated Cl- conductance that is molecularly distinct from CFTR; and (ii) the level of expression of this alternative Cl- conductance in the epithelium is an important determinant of the severity of organ-level disease in CF.

Citing Articles

The enigmatic SLC26A6 multifunctional anion transporter: recent advances in structure-function relationship, pathophysiological significance and novel pharmacological inhibitors.

Seidler U Front Pharmacol. 2025; 15:1536864.

PMID: 39949394 PMC: 11821980. DOI: 10.3389/fphar.2024.1536864.

Assessing the consistency of iPSC and animal models in cystic fibrosis modelling: A meta-analysis.

Darwish T, Al-Khulaifi A, Ali M, Mowafy R, Arredouani A, Doi S PLoS One. 2022; 17(8):e0272091.

PMID: 35944004 PMC: 9362911. DOI: 10.1371/journal.pone.0272091.

Function and Regulation of the Calcium-Activated Chloride Channel Anoctamin 1 (TMEM16A).

Arreola J, Perez-Cornejo P, Segura-Covarrubias G, Corral-Fernandez N, Leon-Aparicio D, Guzman-Hernandez M Handb Exp Pharmacol. 2022; 283:101-151.

PMID: 35768554 DOI: 10.1007/164_2022_592.

Investigating the Implications of Exon Skipping Using a Exon 9 Deleted Mouse Model.

Martinovich K, Kicic A, Stick S, Johnsen R, Fletcher S, Wilton S Front Pharmacol. 2022; 13:868863.

PMID: 35392567 PMC: 8981082. DOI: 10.3389/fphar.2022.868863.

Methodological tools to study species of the genus Burkholderia.

Scoffone V, Trespidi G, Barbieri G, Irudal S, Israyilova A, Buroni S Appl Microbiol Biotechnol. 2021; 105(24):9019-9034.

PMID: 34755214 PMC: 8578011. DOI: 10.1007/s00253-021-11667-3.

References

Devor D, Simasko S, Duffey M . Carbachol induces oscillations of membrane potassium conductance in a colonic cell line, T84. Am J Physiol. 1990; 258(2 Pt 1):C318-26. DOI: 10.1152/ajpcell.1990.258.2.C318. View

de Jonge H, Van den Berghe N, Tilly B, Kansen M, Bijman J . (Dys)regulation of epithelial chloride channels. Biochem Soc Trans. 1989; 17(5):816-8. DOI: 10.1042/bst0170816. View

OLoughlin E, Hunt D, Gaskin K, Stiel D, Bruzuszcak I, Martin H . Abnormal epithelial transport in cystic fibrosis jejunum. Am J Physiol. 1991; 260(5 Pt 1):G758-63. DOI: 10.1152/ajpgi.1991.260.5.G758. View

Barasch J, Kiss B, Prince A, Saiman L, Gruenert D, Al-Awqati Q . Defective acidification of intracellular organelles in cystic fibrosis. Nature. 1991; 352(6330):70-3. DOI: 10.1038/352070a0. View

Anderson M, Welsh M . Calcium and cAMP activate different chloride channels in the apical membrane of normal and cystic fibrosis epithelia. Proc Natl Acad Sci U S A. 1991; 88(14):6003-7. PMC: 52010. DOI: 10.1073/pnas.88.14.6003. View

Anderson M, Gregory R, Thompson S, Souza D, Paul S, Mulligan R . Demonstration that CFTR is a chloride channel by alteration of its anion selectivity. Science. 1991; 253(5016):202-5. DOI: 10.1126/science.1712984. View

Knowles M, Clarke L, Boucher R . Activation by extracellular nucleotides of chloride secretion in the airway epithelia of patients with cystic fibrosis. N Engl J Med. 1991; 325(8):533-8. DOI: 10.1056/NEJM199108223250802. View

Goldstein J, Shapiro A, Rao M, Layden T . In vivo evidence of altered chloride but not potassium secretion in cystic fibrosis rectal mucosa. Gastroenterology. 1991; 101(4):1012-9. DOI: 10.1016/0016-5085(91)90728-4. View

Shoshani T, Augarten A, Gazit E, Bashan N, Yahav Y, Rivlin Y . Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease. Am J Hum Genet. 1992; 50(1):222-8. PMC: 1682509. View

10.

Bear C, Li C, Kartner N, Bridges R, Jensen T, Ramjeesingh M . Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR). Cell. 1992; 68(4):809-18. DOI: 10.1016/0092-8674(92)90155-6. View

11.

Snouwaert J, Brigman K, Latour A, Malouf N, Boucher R, SMITHIES O . An animal model for cystic fibrosis made by gene targeting. Science. 1992; 257(5073):1083-8. DOI: 10.1126/science.257.5073.1083. View

12.

Clarke L, Grubb B, Gabriel S, SMITHIES O, Koller B, Boucher R . Defective epithelial chloride transport in a gene-targeted mouse model of cystic fibrosis. Science. 1992; 257(5073):1125-8. DOI: 10.1126/science.257.5073.1125. View

13.

Clarke L, Boucher R . Chloride secretory response to extracellular ATP in human normal and cystic fibrosis nasal epithelia. Am J Physiol. 1992; 263(2 Pt 1):C348-56. DOI: 10.1152/ajpcell.1992.263.2.C348. View

14.

Cartwright C, McRoberts J, Mandel K, Dharmsathaphorn K . Synergistic action of cyclic adenosine monophosphate- and calcium-mediated chloride secretion in a colonic epithelial cell line. J Clin Invest. 1985; 76(5):1837-42. PMC: 424220. DOI: 10.1172/JCI112176. View

15.

Githens 3rd S, Holmquist D, Whelan J, Ruby J . Ducts of the rat pancreas in a agarose matrix culture. In Vitro. 1980; 16(9):797-808. DOI: 10.1007/BF02619315. View

16.

Clarke L, Burns K, Bayle J, Boucher R, Van Scott M . Sodium- and chloride-conductive pathways in cultured mouse tracheal epithelium. Am J Physiol. 1992; 263(5 Pt 1):L519-25. DOI: 10.1152/ajplung.1992.263.5.L519. View

17.

Berschneider H, Knowles M, Azizkhan R, Boucher R, Tobey N, Orlando R . Altered intestinal chloride transport in cystic fibrosis. FASEB J. 1988; 2(10):2625-9. DOI: 10.1096/fasebj.2.10.2838365. View

18.

Taylor C, Baxter P, Hardcastle J, Hardcastle P . Failure to induce secretion in jejunal biopsies from children with cystic fibrosis. Gut. 1988; 29(7):957-62. PMC: 1433757. DOI: 10.1136/gut.29.7.957. View

19.

Willumsen N, Davis C, Boucher R . Intracellular Cl- activity and cellular Cl- pathways in cultured human airway epithelium. Am J Physiol. 1989; 256(5 Pt 1):C1033-44. DOI: 10.1152/ajpcell.1989.256.5.C1033. View

20.

Willumsen N, Boucher R . Shunt resistance and ion permeabilities in normal and cystic fibrosis airway epithelia. Am J Physiol. 1989; 256(5 Pt 1):C1054-63. DOI: 10.1152/ajpcell.1989.256.5.C1054. View