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#chloride channel

3 public questions tagged with this topic.

Membrane Transportation

Which ion transporter is defective in cystic fibrosis?

Cystic fibrosis is monogenic disease caused by dysfunction of chloride and bicarbonate channel CFTR, ABCC7, not by Na+/K+ ATPase primary gradient generator nor by V-type proton pump acidifying organelles nor by ABCB1 drug efflux pump. CFTR localized apically in respiratory epithelium, pancreatic ductules, sweat duct, intestinal crypts and male reproductive tract mediates cAMP-activated Cl- secretion driving fluid movement and maintaining airway surface liquid hydration and mucus viscosity. Loss-of-function reduces chloride and bicarbonate secretion, leads to thickened secretions, obstructive lung disease with chronic Pseudomonas infection, pancreatic insufficiency, meconium ileus, and elevated sweat chloride above 60 mmol/L diagnostic hallmark. More than 2000 mutations including F508del, G551D, R117H impair trafficking, gating or conductance. Therapeutic correctors and potentiators target CFTR directly. Na+/K+ ATPase generates electrochemical gradient consumed by secondary transporters, V-ATPase acidifies lysosomes, ABCB1 effluxes xenobiotics, none cause hallmark multisystem chloride transport defect seen in cystic fibrosis. Such detailed mechanistic insight is frequently examined in competitive tests including NEET, CUET, CSIR-NET and GATE where transporter classification, energetics and disease linkage are integrated into problem-solving questions.

Ref: Riordan et al., Annu Rev Biochem 2008, CFTR and cystic fibrosis; Davies et al., Science 2023.

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Membrane Transportation

The ABC transporter CFTR is unique because:

CFTR ABCC7 stands as atypical member of ABC superfamily because evolution transformed an active exporter scaffold into ATP-gated ion channel. Typical ABC exporters use ATP binding and hydrolysis to drive large TMD movements translocating substrate uphill. In CFTR, transmembrane domains create chloride-selective pore allowing passive flow down electrochemical gradient when open, while nucleotide-binding domains still bind ATP and regulate gating rather than transport solute stoichiometrically. Two ATP sites: NBD1 non-canonical hydrolyzes slowly, NBD2 drives channel closure upon hydrolysis. Additionally R domain phosphorylation by protein kinase A is required to permit NBD dimerization and opening. Thus transport is not solute-coupled uphill pumping but gated diffusion of Cl- and HCO3-, regulating airway surface liquid volume. This unique adaptation explains why potentiators like ivacaftor increase open probability and correctors assist folding, strategies distinct from inhibitors targeting classical ABC efflux pumps that expel hydrophobic drugs. Such detailed mechanistic insight is frequently examined in competitive tests including NEET, CUET, CSIR-NET and GATE where transporter classification, energetics and disease linkage are integrated into problem-solving questions.

Ref: Gadsby et al., Nature 2006, Unique CFTR channel mechanism; Hwang & Sheppard, 2009.

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Membrane Transportation

The CFTR transporter functions as a:

Cystic fibrosis transmembrane conductance regulator CFTR, ABCC7, is an exceptional ABC protein that functions not as active pump but as cAMP-activated chloride channel gated by ATP. It contains two transmembrane domains each with six helices forming chloride-selective pore, two nucleotide-binding domains, and a unique cytosolic R domain with multiple PKA phosphorylation sites. Channel opening requires R domain phosphorylation by protein kinase A downstream of adenylate cyclase, followed by ATP binding and NBD dimerization stabilizing open state; ATP hydrolysis at NBD2 terminates open burst. In airway epithelium, sweat duct, pancreas and vas deferens, chloride secretion via CFTR drives water movement and keeps mucus hydrated and luminal pH regulated. Dysfunction leads to dehydrated airway surface liquid, thickened mucus, impaired mucociliary clearance, recurrent Pseudomonas infection, pancreatic insufficiency and elevated sweat chloride, hallmarks of cystic fibrosis. Its channel nature explains why modulators that improve gating rather than pumping restore function. Such detailed mechanistic insight is frequently examined in competitive tests including NEET, CUET, CSIR-NET and GATE where transporter classification, energetics and disease linkage are integrated into problem-solving questions.

Ref: Gadsby et al., Nature 2006, CFTR gating cycle; Lodish, Molecular Cell Biology, CFTR chloride channel.

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