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PKA stimulates CFTR channels through two mechanisms: non\u2010catalytically, by binding to the channel, and catalytically, by phosphorylating its regulatory (R) domain. CFTR mutations that reduce channel activity cause cystic fibrosis (CF), but clinically used modulator drugs that boost channel function can alleviate disease symptoms. The two common CF mutations, \u0394F508 and G551D, have been reported to impair CFTR channel activation by PKA, but the mechanisms remain unclear. Here, we aimed to understand how the mutations impact non\u2010catalytic\n                      <jats:italic>vs<\/jats:italic>\n                      . catalytic channel activation by PKA and how these two processes are modulated by clinically used potentiator drugs. Using current recordings from excised inside\u2010out membrane patches superfused with the purified catalytic subunit of PKA, we confirm slowed PKA\u2010dependent activation for both mutants but demonstrate intact binding affinity for the kinase. Furthermore, we find that non\u2010catalytic activation dominates overall channel activity for both mutants and can be strongly enhanced by stabilization of the NBD1\u2013NBD2\u2013TMD interface using the ATP analogue\n                      <jats:italic>N<\/jats:italic>\n                      <jats:sup>6<\/jats:sup>\n                      \u2010(2\u2010phenylethyl)\u2010ATP. For both mutants, the clinically used potentiator drug combination elexacaftor\u00a0+\u00a0ivacaftor boosts catalytic channel activation by PKA more efficiently than non\u2010catalytic activation. For \u0394F508 CFTR, elexacaftor\u00a0+\u00a0ivacaftor evokes substantial PKA\u2010independent channel activity and entirely suppresses non\u2010catalytic 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.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp70483-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Protein kinase A (PKA) activates the epithelial anion channel cystic fibrosis transmembrane conductance regulator (CFTR) through two mechanisms: non\u2010catalytically, by binding to the channel, and catalytically, by phosphorylating its regulatory (R) domain.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>CFTR mutations cause cystic fibrosis (CF); the two common mutations, \u0394F508 and G551D, reportedly also impair channel activation by PKA.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>We show here, for both mutants, that PKA\u2010dependent activation is slowed despite intact binding affinity for the kinase, and that non\u2010catalytic activation dominates overall channel activity and might be further enhanced by stabilization of the NBD1\u2013NBD2\u2013TMD interface.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>For \u0394F508 CFTR, but not for G551D CFTR, a combination of clinically used potentiator drugs evokes substantial PKA\u2010independent channel activity but suppresses non\u2010catalytic activation by PKA.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>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.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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