Commentary Cystic Fibrosis Transmembrane Conductance Regulator

In the 8 yr since the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) was identified by means of positional cloning (Kerem et al., 1989; Riordan et al., 1989; Rommens et al., 1989), the Cl channel function of CFTR has been studied in a wide variety of expression systems. Macroscopic and single-channel currents have been measured and a large number of mutant constructs containing either single amino acid substitutions or major deletions have been examined. It is ironic, however, that despite this intense activity, there is little available in the published literature in the way of a systematic characterization of the conduction properties of this unique Cl channel. In this issue of The Journal of General Physiology , John Hanrahan and his colleagues make an important contribution to this question in the form of three papers in which they report experimental and modeling results pertaining to anion permeation. Although it seems unlikely that these papers will attract the same attention as the cloning of farm animals or new approaches to gene therapy, they contain information that is crucial to developing an understanding of the Cl permeation mechanism of CFTR; and the results extend the functional fingerprint of the channel in a way that will be useful to other investigators seeking to identify CFTR channels (e.g., in reconstituted systems). The amino acid sequence of the CFTR protein and its predicted topology accurately foreshadowed the regulation of CFTR channel function by phosphorylation and ATP binding/hydrolysis (Kerem et al. but the primary structure provided no hint as to the nature of the anion conduction path. There is no homology or internal symmetry to suggest how the 12 membrane-spanning segments might be arranged to form a pore, although the abundance of patient mutations provides clues as to specific residues that might be important for pore function (Anderson et al. The difficulty in probing pore structure is compounded by the fact that CFTR, expressed predominantly in epithelial cells, does not appear to be a target for the sorts of highly specific toxins that have been so useful in deciphering the conduction properties of voltage-gated channels. Although several compounds have been advanced as blockers of the CFTR, it nevertheless appears that the best probes of the pore are, in fact, permeant anions that must, by definition, enter, traverse, and interact with the conduction path. In this regard, the study of CFTR conduction is well endowed …