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Revisiting Cystic Fibrosis Transmembrane Conductance Regulator Structure and Function

Department of Physiology, McGill University, Montreal, Quebec, Canada

Correspondence and requests for reprints should be addressed to John W. Hanrahan, Ph.D., McGill University, Department of Physiology, 3655 Promenade, Sir William Osler McIntyre Medical Science Building, H3G 1Y6 Montreal, Quebec, Canada. E-mail: john.hanrahan{at}mcgill.ca

The cystic fibrosis transmembrane conductance regulator (CFTR) is a channel/enzyme which mediates passive diffusion of chloride and bicarbonate through epithelial cell membranes. It is expressed in many cell types throughout the body, but in the airways it is found mainly in secretory serous cells of the submucosal glands. CFTR belongs to a large super-family of ATP binding cassette transporters that have two nucleotide binding domains with characteristic sequences or "motifs." Although most other ATP binding cassette transporters consume ATP to actively transport various substrates, in CFTR the interactions of ATP with nucleotide binding domains control opening and closing of the channel pore (i.e., channel gating). Recent high resolution structures of bacterial nucleotide binding domains combined with new biochemical and electrophysiological studies of CFTR itself have led to major advances in our understanding of CFTR gating. For example, it is now clear that the ATPase activity of CFTR is not strictly required for its channel activity. CFTR has at least two distinct gating modes; one dependent on hydrolysis and the other requiring only stable ATP binding. In this article we discuss a working hypothesis for CFTR that incorporates these recent findings and discuss some interesting implications of the paradigm shift for other aspects of CFTR function and dysfunction.

Key Words: cystic fibrosis • chloride secretion • nucleotide binding domains • channel gating

This article has been cited by other articles:

				T.-Y. Chen and T.-C. Hwang CLC-0 and CFTR: Chloride Channels Evolved From Transporters Physiol Rev, April 1, 2008; 88(2): 351 - 387. [Abstract] [Full Text] [PDF]