Table 2.

Effects of CFTR modulators on PKA-dependent regulation of CFTR mutants.

CFTR mutant	Impact on PKA-mediated phosphorylation	Effects of CFTR modulators	References
F508del	Reduced phosphorylation rate (PKA phospho-sites S442, S660), altered interaction with 14-3-3 proteins, increased COPI-mediated retrograde trafficking, defective PKA-regulated exocytosis	Potentiation by VX-770 shows contrasting results on phosphorylated and non-phosphorylated mutant CFTR. VX-770-mediated rescue requires S442, while its deletion enhances VX-809 correction. The activator UCCF-152 potentiates the phosphorylation of the R domain	Wang et al., 2000; Pasyk et al., 2009; Pyle et al., 2011; Eckford et al., 2012; Liang et al., 2012; Holleran et al., 2013; Uliyakina et al., 2020
G551D	Reduced phosphorylation (PKA phospho-site S737) and defective phosphorylation-dependent activation	VRT-532 potentiates the activity of the channel. The activator UCCF-152 potentiates the phosphorylation of the R domain	Chang et al., 1993; Pyle et al., 2011; Wang et al., 2020