Altered functional interactions between CFTR disease mutants ΔF508 and G551D and the protein kinase A catalytic subunit

-(2-phenylethyl)-ATP. For both mutants, the clinically used potentiator drug combination elexacaftor + ivacaftor boosts catalytic channel activation by PKA more efficiently than non-catalytic activation. For ΔF508 CFTR, elexacaftor + ivacaftor evokes substantial PKA-independent channel activity and entirely suppresses non-catalytic activation by PKA. These findings help us to understand the activation defects caused by two common CF mutations and suggest room for further improvement of potentiator drugs currently used in CF therapy. KEY POINTS: Protein kinase A (PKA) activates the epithelial anion channel cystic fibrosis transmembrane conductance regulator (CFTR) through two mechanisms: non-catalytically, by binding to the channel, and catalytically, by phosphorylating its regulatory (R) domain. CFTR mutations cause cystic fibrosis (CF); the two common mutations, ΔF508 and G551D, reportedly also impair channel activation by PKA. We show here, for both mutants, that PKA-dependent activation is slowed despite intact binding affinity for the kinase, and that non-catalytic activation dominates overall channel activity and might be further enhanced by stabilization of the NBD1-NBD2-TMD interface. For ΔF508 CFTR, but not for G551D CFTR, a combination of clinically used potentiator drugs evokes substantial PKA-independent channel activity but suppresses non-catalytic activation by PKA. These findings help us to understand the activation defects caused by two common CF mutations and suggest room for further improvement of potentiator drugs currently used in CF therapy.