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Cystic Fibrosis and Gastric Acid Transport

Cystic Fibrosis and Gastric Acid Transport. March 11, 2008 CH353 Group Project Sidani et al. 2007, DeltaF508 mutation results in impaired gastric acid secretion, J. Biol. Chem. 282(9): 6068-74. Background on Cystic Fibrosis.

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Cystic Fibrosis and Gastric Acid Transport

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  1. Cystic Fibrosis and Gastric Acid Transport March 11, 2008 CH353 Group Project Sidani et al. 2007, DeltaF508 mutation results in impaired gastric acid secretion, J. Biol. Chem. 282(9): 6068-74.

  2. Background on Cystic Fibrosis • Cystic Fibrosis is prevalent genetic disorder affecting individuals of predominantly European descent • Autosomal recessive disorder 1/25 of population are carriers • CF carriers may be resistant to cholera (analogous to sickle cell anemia and malaria) • CF is caused by genetic impairment of CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) • ~70% of CF patients have the codon deletion ∆F508 • CF causes impairment of respiratory tract and exocrine glands and ducts; impaired chloride transport

  3. Membrane Topology of CFTR • CFTR resembles an ABC transporter • 2 transmembrane domains (6 helices) • 2 nucleotide binding domains (NBD) • Cl– channel controlled by ATP mediated dimerization of NBDs • Unique regulatory (R) domain is phosphorylated by various kinases • One is protein kinase A (PKA), which is activated by cAMP • ∆F508 mutation is in NBD1; altered CFTR protein folds incorrectly

  4. Activation of CFTR • Activation of CFTR Cl– channel with ATP and protein kinase A • Patch clamping data showing opening and closing of Cl– channels • Model for activation of CFTR with ATP • ATP binding opens • ATP hydrolysis closes • One ATP is hydrolyzed the other remains bound

  5. Proposed Structure of CFTR • Actual 3D structure is unknown • Model devised from fitting of CFTR amino acid sequence to an ABC transporter structure • The structure of the regulatory domain Rd has no model (red dots indicate insertion points) • Helix 6 (yellow) is proposed anion channel • K334 and K335 possibly bind anions outside

  6. CFTR and Gastric Acid Transport • CFTR regulates the function of epithelial ion channels • Gastric parietal cells secrete HCl into stomach • H+K+ ATPase responsible for acidifying gastric fluid • Hypothesis: CFTR is involved in regulating H+K+ ATPase

  7. Group Study Problem • Which transporters are involved in gastric acid secretion? What types of transporters? • How is H+K+ ATPase regulated? List neuroendocrine secretagogues and intracellular mechanism. • Which inhibitors/activators were used in these experiments? What are their targets? • Draw a schematic of transporters in gastric parietal cells, indicating apical and basolateral positions.

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