Ten years with CFTR.

how the loss of this chloride channel pathway contributes This is the second single-topic supplement to Physioto the multiple manifestations of CF in diverse organ syslogical Reviews. In introducing the first supplement, Dantems. In this collection of works, we attempt to remain iel Gardner indicated that the articles reported on the focused on essential physiological issues concerning the progress of a revolution, first recognized by the series function of CFTR. Therefore, little information is provided of papers on membrane currents in nerve published by on CF genetics, and there is only a brief treatment of Hodgkin, Huxley, and colleagues. This supplement reports human genotype-phenotype correlations (5). For these on another revolution in cell physiology and on what is subjects, the interested reader is referred to several excelprobably one of the most intensely studied proteins in lent reviews (1, 3, 9). Rather, we focus on the ‘‘nuts and biomedical science: the cystic fibrosis transmembrane bolts’’ of CFTR and its contribution to epithelial cell funcconductance regulator (CFTR). It is now 10 years since tion. identification of the gene responsible for cystic fibrosis Paul Quinton begins this series with a personal ac(CF) was announced (2, 7, 8); these papers reported not count of the physiological basis of CF that includes not only the chromosomal mapping and sequence of the gene only historical perspectives but also valuable reflections and its protein product but also an amazingly accurate on the complex events that attend deletion of the cAMPprediction of CFTR’s secondary structure (7). Lap Chee regulated chloride conductance in epithelial cells. Paul Tsui, John Riordan, and Francis Collins included in their takes us through the critical transition from ‘‘witches to appellation, CFTR, the terms conductance and regulator, science,’’ which he has personally witnessed and to which descriptors that the subsequent years’ investigations, and his important work has contributed. David Sheppard and the articles in this supplement, show aptly to apply. Michael Welsh review the structure-function relations of In the period B.C., that is, before cloning of the CFTR the CFTR chloride channel. They provide a functional gene, our understanding of the cellular implications of CF survey of the significant domain structures of CFTR and gene mutations was fairly well developed. We understood the manner in which they relate to chloride channel gatthat CF was a disease of epithelial cells and that its celluing. David Dawson, Steven Smith, and Monique Mansoura lar phenotype omitted a cAMP-regulated chloride conducprovide us with a detailed look at CFTR’s conduction tance pathway that was crucial for the salt and water pathway for chloride ions. They describe the structural secretory response of many epithelial tissues. We underbasis of anion selectivity and the way in which both disstood that the impairment of epithelial chloride conducease and experimental mutations have contributed to our tance extended to channels localized in membrane fragcurrent understanding of the conduction pathway. David ments at the ends of patch pipettes. The pioneering work Gadsby and Angus Nairn focus their review on the control of Quinton (6), Knowles et al. (4), and other colleagues of CFTR channel gating by phosphorylation and nucleocreated a sea change, not only in our understanding of the tide hydrolysis. Their review details the unique position CF phenotype but also in the numbers of skilled scientists occupied by the CFTR chloride channel in the ABC (ATPwilling to devote significant effort to this protein and the binding cassette) superfamily of transporters; they prodisease that it defines. In the period A.C., after cloning, vide a model that utilizes coordinated nucleotide hydrolythis momentum has exploded, as a tangible and manipusis to effect channel opening and closing rather than orlatable entity was provided to explore the array of cellular ganic solute transport. They also review the control of processes on which CFTR touches. Indeed, this proliferaCFTR by kinase and phosphatase-mediated R-domain tion is so extensive that detailed chapters can now be phosphorylation in relation to its channel-gating funcwritten on subjects as focused as the conduction and gating properties of CFTR. Evidence supporting the idea that tions. Bruce Schultz, Ashvani Singh, Daniel Devor, and Robert Bridges describe the pharmacology of CFTR. Their CFTR functions as a regulated chloride channel quickly emerged in the period A.C., largely as a result of our exdetailed overview of compounds that modulate the chloride channel activity of CFTR should be a valuable field isting understanding of the physiology of CF epithelial cells. To be sure, we are still trying to fully appreciate guide for those who are brave enough to approach studies