The SLC26A9 inhibitor S9‐A13 provides no evidence for a role of SLC26A9 in airway chloride secretion but suggests a contribution to regulation of ASL pH and gastric proton secretion

URN to cite this document:

urn:nbn:de:bvb:355-epub-530031 Copy

DOI to cite this document:

10.5283/epub.53003 Copy

Jo, Sungwoo ; Centeio, Raquel ; Park, Jinhong ; Ousingsawat, Jiraporn ; Jeon, Dong‐kyu ; Talbi, Khaoula ; Schreiber, Rainer ; Ryu, Kunhi ; Kahlenberg, Kristin ; Somoza, Veronika ; Delpiano, Livia ; Gray, Michael A. ; Amaral, Margarida D. ; Railean, Violeta ; Beekman, Jeffrey M. ; Rodenburg, Lisa W. ; Namkung, Wan ; Kunzelmann, Karl

License: Creative Commons Attribution Non-commercial No Derivatives 4.0 PDF - Published Version (10MB)

Date of publication of this fulltext: 12 Oct 2022 04:48

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Details

Item type:	Article
Open Access Type:	DEAL (Wiley)
Journal or Publication Title:	The FASEB Journal
Publisher:	Wiley
Volume:	36
Number of Issue or Book Chapter:	11
Page Range:	e22534
Date:	2 October 2022
Institutions:	Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Karl Kunzelmann
Projects:	DFG KU756/14-1
Identification Number:	Value Type 10.1096/fj.202200313RR DOI
Keywords:	airways, asthma, Cl− secretion, cystic fibrosis, pH regulation, S9-A13, SLC26A9
Dewey Decimal Classification:	500 Science > 570 Life sciences
Status:	Published
Refereed:	Yes, this version has been refereed
Created at the University of Regensburg:	Partially
Item ID:	53003

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Abstract

The solute carrier 26 family member A9 (SLC26A9) is an epithelial anion transporter that is assumed to contribute to airway chloride secretion and surface hydration. Whether SLC26A9 or CFTR is responsible for airway Cl− transport under basal conditions is still unclear, due to the lack of a specific inhibitor for SLC26A9. In the present study, we report a novel potent and specific inhibitor for ...

Abstract

The solute carrier 26 family member A9 (SLC26A9) is an epithelial anion transporter that is assumed to contribute to airway chloride secretion and surface hydration. Whether SLC26A9 or CFTR is responsible for airway Cl− transport under basal conditions is still unclear, due to the lack of a specific inhibitor for SLC26A9. In the present study, we report a novel potent and specific inhibitor for SLC26A9, identified by screening of a drug-like molecule library and subsequent chemical modifications. The most potent compound S9-A13 inhibited SLC26A9 with an IC50 of 90.9 ± 13.4 nM. S9-A13 did not inhibit other members of the SLC26 family and had no effects on Cl− channels such as CFTR, TMEM16A, or VRAC. S9-A13 inhibited SLC26A9 Cl− currents in cells that lack expression of CFTR. It also inhibited proton secretion by HGT-1 human gastric cells. In contrast, S9-A13 had minimal effects on ion transport in human airway epithelia and mouse trachea, despite clear expression of SLC26A9 in the apical membrane of ciliated cells. In both tissues, basal and stimulated Cl− secretion was due to CFTR, while acidification of airway surface liquid by S9-A13 suggests a role of SLC26A9 for airway bicarbonate secretion.

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Metadata last modified: 06 Jul 2023 13:39

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