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Aberrant CFTR-dependent HCO-3 transport in mutations associated with cystic fibrosis

Nature volume 410, pages 94–97 (2001)Cite this article

Abstract

Cystic fibrosis (CF) is a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Initially, Cl- conductance in the sweat duct was discovered to be impaired in CF1, a finding that has been extended to all CFTR-expressing cells2,3,4. Subsequent cloning of the gene5,6 showed that CFTR functions as a cyclic-AMP-regulated Cl- channel7; and some CF-causing mutations inhibit CFTR Cl- channel activity2,3,4,8. The identification of additional CF-causing mutants with normal Cl- channel activity indicates, however, that other CFTR-dependent processes contribute to the disease. Indeed, CFTR regulates other transporters3,4, including Cl--coupled HCO-3 transport9,10. Alkaline fluids are secreted by normal tissues, whereas acidic fluids are secreted by mutant CFTR-expressing tissues11, indicating the importance of this activity. HCO-3 and pH affect mucin viscosity12,13 and bacterial binding14,15. We have examined Cl--coupled HCO-3 transport by CFTR mutants that retain substantial or normal Cl- channel activity. Here we show that mutants reported to be associated with CF with pancreatic insufficiency do not support HCO-3 transport, and those associated with pancreatic sufficiency show reduced HCO-3 transport. Our findings demonstrate the importance of HCO-3 transport in the function of secretory epithelia and in CF.

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Figure 1: AMP-stimulated Cl- and HCO-3 transport by wild-type (WT) CFTR and the CFTR mutants I148T and R117H.
Figure 3: The HCO-3:Cl- transport ratio of CFTR mutants associated with CF.
Figure 2: AMP-stimulated Cl- and HCO-3 transport by CFTR mutants associated with a severe or a mild form of CF. [Cl-]i (a, b, e, f) and HCO-3 (c, d, g, h) transport were measured as in Fig. 1.

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Acknowledgements

We thank H. Cuppens from the European CF Consortium for informing us that the G970R mutation results in pancreatic insufficiency. This work was supported by a grant from the NIH.

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Authors and Affiliations

  1. Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Joo Young Choi, Daniella Muallem, Kirill Kiselyov, Philip J. Thomas & Shmuel Muallem

  2. Department of Pharmacology and Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, 120-752, Korea

    Min Goo Lee

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Correspondence to Shmuel Muallem.

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Choi, J., Muallem, D., Kiselyov, K. et al. Aberrant CFTR-dependent HCO-3 transport in mutations associated with cystic fibrosis. Nature 410, 94–97 (2001). https://doi.org/10.1038/35065099

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