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Control of dynamic CFTR selectivity by glutamate and ATP in epithelial cells


Cystic fibrosis is caused by mutations in cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel1. Phosphorylation and ATP hydrolysis are generally believed to be indispensable for activating CFTR2. Here we report phosphorylation- and ATP-independent activation of CFTR by cytoplasmic glutamate that exclusively elicits Cl-, but not HCO3-, conductance in the human sweat duct. We also report that the anion selectivity of glutamate-activated CFTR is not intrinsically fixed, but can undergo a dynamic shift to conduct HCO3- by a process involving ATP hydrolysis. Duct cells from patients with ΔF508 mutant CFTR showed no glutamate/ATP activated Cl- or HCO3- conductance. In contrast, duct cells from heterozygous patients with R117H/ΔF508 mutant CFTR also lost most of the Cl- conductance, yet retained significant HCO3- conductance. Hence, not only does glutamate control neuronal ion channels, as is well known, but it can also regulate anion conductance and selectivity of CFTR in native epithelial cells. The loss of this uniquely regulated HCO3- conductance is most probably responsible for the more severe forms of cystic fibrosis pathology.

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Figure 1: Effect of cytoplasmic glutamate on CFTR-gCl.
Figure 2: Effect of ATP on the HCO3- selectivity of glutamate-activated CFTR.
Figure 3: Effect of ATP and AMP-PNP on CFTR - g HCO 3 .
Figure 4: Effect of CFTR mutations on CFTR-gCl and CFTR - g HCO 3 .


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We thank K. Taylor and S. Madireddi for technical assistance, A. Ponce for reverse transcriptase polymerase chain reaction, and M. Pian, D. Conrad, C. Nagy, A. Wallace and M. Farrel for assistance in securing specimens from normal and cystic fibrosis patients. This work was funded by grants from the USPHS-NIH, the CF Foundation, the Olmsted Trust, the Gillette Co. and the Texaco Foundation.

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Correspondence to M. M. Reddy.

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Reddy, M., Quinton, P. Control of dynamic CFTR selectivity by glutamate and ATP in epithelial cells. Nature 423, 756–760 (2003).

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