Anchored PDE4 regulates chloride conductance in wild-type and ΔF508-CFTR human airway epithelia.

Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmem-brane conductance regulator (CFTR) that impair its expression and/or chloride channel function. Here, we provide evidence that type 4 cyclic nucleotide phos-phodiesterases (PDE4s) are critical regulators of the cAMP/PKA-dependent activation of CFTR in primary human bronchial epithelial cells. In non-CF cells, PDE4 inhibition increased CFTR activity under basal conditions (ΔI_SC 7.1 µA/cm²) and after isoproterenol stimulation (increased ΔI_SC from 13.9 to 21.0 (µA/cm²) and slowed the return of stimulated CFTR activity to basal levels by > 3-fold. In cells homozygous for ΔF508-CFTR, the most common mutation found in CF, PDE4 inhibition alone produced minimal channel activation. However, PDE4 inhibition strongly amplified the effects of CFTR correctors, drugs that increase expression and membrane localization of CFTR, and/or CFTR poten-tiators, drugs that increase channel gating, to reach ~ 25% of the chloride conductance observed in non-CF cells. Biochemical studies indicate that PDE4s are anchored to CFTR and mediate a local regulation of channel function. Taken together, our results implicate PDE4 as an important determinant of CFTR activity in airway epithelia, and support the use of PDE4 inhibitors to potentiate the therapeutic benefits of CFTR correctors and potentiators. [ABSTRACT FROM AUTHOR]