Anchored PDE4 controls CFTR conductance in normal and cystic fibrosis airway epithelia (1181.3)

Abstract

Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that impair its expression or function. PKA phosphorylation is the main mechanism to activate CFTR. However, previous reports indicated that cAMP/PKA activators are ineffective in restoring CFTR conductance in CF epithelia. Our current findings challenge this conclusion. We show that inhibition of type 4 cAMP‐phosphodiesterases (PDE4s) increased CFTR activity in non‐CF primary human bronchial epithelial cells under basal conditions and after β‐adrenergic stimulation, and slowed the return of stimulated CFTR activity to basal levels. In cells homozygous for ∆F508‐CFTR, the most common mutation found in CF patients, 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 CFTR potentiators, 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 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. Grant Funding Source: Supported by the Cystic Fibrosis Foundation, the NIH, and Cystic Fibrosis Research Inc.