Calcium-pump inhibitors induce functional surface expression of δf508-cftr protein in cystic fibrosis epithelial cells

ABSTRACT The most common mutation in cystic fibrosis, ΔF508, results in a cystic fibrosis transmembrane conductance regulator (CFTR) protein that is retained in the endoplasmic reticulum

(ER). Retention is dependent upon chaperone proteins, many of which require Ca++ for optimal activity. Interfering with chaperone activity by depleting ER Ca++ stores might allow functional

ΔF508-CFTR to reach the cell surface. We exposed several cystic fibrosis cell lines to the ER Ca++ pump inhibitor thapsigargin and evaluated surface expression of ΔF508-CFTR. Treatment

released ER-retained ΔF508-CFTR to the plasma membrane, where it functioned effectively as a Cl− channel. Treatment with aerosolized calcium-pump inhibitors reversed the nasal epithelial

potential defect observed in a mouse model of ΔF508-CFTR expression. Thus, ER calcium-pump inhibitors represent a potential target for correcting the cystic fibrosis defect. Access through

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CONTENT BEING VIEWED BY OTHERS SARS-COV-2 VIRAL ENTRY AND REPLICATION IS IMPAIRED IN CYSTIC FIBROSIS AIRWAYS DUE TO ACE2 DOWNREGULATION Article Open access 10 January 2023 SFPQ RESCUES

F508DEL-CFTR EXPRESSION AND FUNCTION IN CYSTIC FIBROSIS BRONCHIAL EPITHELIAL CELLS Article Open access 17 August 2021 MACROCYCLE-STABILIZATION OF ITS INTERACTION WITH 14-3-3 INCREASES PLASMA

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Scholar  Download references ACKNOWLEDGEMENTS We thank M. Drumm for ΔF508-CFTR mice; W. Guggino, M. Blaustein, P. Aronson, J. Burger, G. Fyfe, G. Giebisch, G. Haddad, P. De Camilli, K.

Bottomly, R. Lifton and members of the Caplan lab group for suggestions and readings of the manuscript; S.A. Mentone for help with electron microscopy; V. Rajendran and M.W. Nason for

technical support; and M. Kashgarian for assistance in evaluating histopathologic specimens. This work was supported by the Alyward Family/Pitney Bowes Gift Fund, Panacea Pharmaceuticals

(M.E.E. and M.J.C.) and by NIH grants DK53428 (to M.E.E.), DK50230 (to J.G.), HD32573 (to J.G.), GM42136 (to M.J.C.) and DK17433 (to J.G. and M.J.C.). AUTHOR INFORMATION Author notes *

Judith Glöckner-Pagel and Catherine A. Ambrose: J.G.-P. and C.A.A. contributed equally to this study. AUTHORS AND AFFILIATIONS * Department of Pediatrics, Yale University School of Medicine,

New Haven, Connecticut, USA Marie E. Egan, Catherine A. Ambrose, Paula A. Cahill, Lamiko Pappoe & Naomi Balamuth * Department of Surgery, Yale University School of Medicine, New Haven,

Connecticut, USA John Geibel * Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA Marie E. Egan, Judith Glöckner-Pagel, Edward

Cho, Susan Canny, Carsten A. Wagner, John Geibel & Michael J. Caplan Authors * Marie E. Egan View author publications You can also search for this author inPubMed Google Scholar * Judith

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Caplan View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Michael J. Caplan. ETHICS DECLARATIONS COMPETING INTERESTS

These studies were supported to a small extent by a sponsored research agreement between Yale University and Panacea Pharmaceuticals, a small biotech firm that has licensed this technology

from Yale University. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Egan, M., Glöckner-Pagel, J., Ambrose, C. _et al._ Calcium-pump inhibitors induce

functional surface expression of ΔF508-CFTR protein in cystic fibrosis epithelial cells. _Nat Med_ 8, 485–492 (2002). https://doi.org/10.1038/nm0502-485 Download citation * Received: 13

March 2002 * Accepted: 29 March 2002 * Issue Date: 01 May 2002 * DOI: https://doi.org/10.1038/nm0502-485 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this

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