Abstract
Defective epithelial ion transport is the hallmark of the common life-limiting genetic disease cystic fibrosis (CF). CF is caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR), an ATP-binding cassette transporter, which functions as an epithelial anion channel regulated by phosphorylation and cycles of ATP binding and hydrolysis. Here, we review selectively the structure and function of CFTR, including how the membrane-spanning domains form an anion-selective pore and the roles of the regulatory domain and nucleotide-binding domains in channel gating. We discuss the development of combination therapy for CF mutations, including CFTR correctors, which rescue misfolding to transport mutant CFTR to the plasma membrane and CFTR potentiators, which increase CFTR activity by enhancing channel gating. Finally, we highlight studies of CFTR processing and membrane trafficking, which identify proteostasis regulators that have the potential to lead to innovative new therapies for CF. Thus, understanding of CFTR has driven new insights into epithelial ion transport and transformed the treatment of CF.
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Acknowledgments
We thank our laboratory colleagues and collaborators for stimulating discussions and assistance and B Kleizen for the generous gift of Fig. 16.3. We are very grateful to T-C Hwang for patch-clamp data (Figs. 16.14 and 16.16) and RJ Bridges for guidance and support. Work in the authors’ laboratories discussed in this manuscript was supported by a postgraduate scholarship from the Government of Oman and grant numbers GRSP/OMC/15/004 and BFP/RGP/HSS/18/030 from the Research Council of Oman (MKAS), Cystic Fibrosis Foundation Therapeutics, Cystic Fibrosis Trust and Medical Research Council (DNS), AbbVie’s CF program (CB and AKS) and Fondazione per la Ricerca sulla Fibrosi Cistica, Italian Ministry of Health (Cinque per mille and Ricerca Corrente—Linea1), and Cystic Fibrosis Foundation (NP).
Conflict of Interest
CB and AKS are employees of AbbVie, Inc. DNS is the recipient of a Vertex Innovation Award from Vertex Pharmaceuticals (Europe) Ltd. All other authors have no conflicts of interest to declare.
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Al Salmani, M.K., Sondo, E., Balut, C., Sheppard, D.N., Singh, A.K., Pedemonte, N. (2020). Molecular Physiology and Pharmacology of the Cystic Fibrosis Transmembrane Conductance Regulator. In: Hamilton, K.L., Devor, D.C. (eds) Studies of Epithelial Transporters and Ion Channels. Physiology in Health and Disease. Springer, Cham. https://doi.org/10.1007/978-3-030-55454-5_16
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