Search

Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel in the ATP binding cassette (ABC) transporter family. Like other ABC transporters, it can hydrolyze ATP. Yet while ATP hydrolysis influences channel gating, it has long seemed puzzling that CFTR would require this reaction because anions flow passively through CFTR. Moreover, no other ion channel is known to require the large energy of ATP hydrolysis to gate. We found that CFTR also has adenylate kinase activity (ATP + AMP ←→ ADP + ADP) that regulates gating. When functioning as an adenylate kinase, CFTR showed positive cooperativity for ATP suggesting its two nucleotide binding domains may dimerize. Thus, channel activity could be regulated by two different enzymatic reactions, ATPase and adenylate kinase, that share a common ATP binding site in the second nucleotide binding domain. At physiologic nucleotide concentrations, adenylate kinase activity, rather than ATPase activity may control gating, and therefore involve little energy consumption. [Copyright &y& Elsevier]

Investigates the activation of G551D cystic fibrosis transmembrane conductance regulator (CFTR) channel with 5-butyl-6-hydroxy-10-chlorobenzo[c]quinolizinium chloride (MPB-91). Methods in the conduct of the study; Effect of protein kinase A and C inhibitors; Role of nucleotide binding domain in MPB-91-mediated CFTR activation.