Revisiting Cystic Fibrosis Transmembrane Conductance Regulator Structure and Function

Abstract

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.

Skeletal Muscle Metabolism in Cystic Fibrosis and Primary Ciliary Dyskinesia

“…The data collection involved MRI followed by shimming (calibration) and 31 P-MRS spectroscopy data acquisition. Adequate recovery after exercise was ensured by monitoring the phosphocreatine (PCr) and inorganic phosphate (Pi) peaks to ensure that they had returned to resting levels.…”

“…31 P metabolite concentrations were calculated by normalizing total muscle phosphate to 41.3 mmol/L (26). Intracellular pH was calculated for each spectrum based on the chemical shift difference between PCr and Pi (27).…”

“…31 P-MRS variables were assessed at rest, and the results were analyzed as the average of 16 resting spectra collected sequentially. There were no differences between groups in resting levels of PCr or Pi or Pi/PCr ratio.…”

“…31 P-MRS results were collected immediately before exercise, after each of ten 30-s exercise bouts and during recovery (Table 4). There were no significant differences in work rates achieved during exercise between the CF and HC groups, but PCD patients exhibited lower watts during the exercise bout (p Ͻ 0.001).…”

“…Recently, [ 31 P]phosphorus magnetic resonance spectroscopy ( 31 P-MRS) to assess muscle metabolism has been used in vivo (13,14) to assess the function of creatine kinase, oxidative phosphorylation, and anaerobic glycolysis pathways during exercise and recovery. 31 P-MRS, in conjunction with specifically designed exercise protocols, may allow for the analysis of metabolism in patients with CF (15).…”