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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

Lookup NU author(s): Livia Delpiano, Dr Michael Gray

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Abstract

© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology. 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.

Publication metadata

Author(s): Jo S, Centeio R, Park J, Ousingsawat J, Jeon D-K, Talbi K, Schreiber R, Ryu K, Kahlenberg K, Somoza V, Delpiano L, Gray MA, Amaral MD, Railean V, Beekman JM, Rodenburg LW, Namkung W, Kunzelmann K

Publication type: Article

Publication status: Published

Journal: FASEB Journal

Year: 2022

Volume: 36

Issue: 11

Print publication date: 01/11/2022

Online publication date: 02/10/2022

Acceptance date: 24/08/2022

Date deposited: 31/10/2022

ISSN (print): 0892-6638

ISSN (electronic): 1530-6860

Publisher: John Wiley & Sons Ltd

URL: https://doi.org/10.1096/fj.202200313RR

DOI: 10.1096/fj.202200313RR

PubMed id: 36183361

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