Related Experiment Video

Updated: Oct 9, 2025

Functional Reconstitution and Channel Activity Measurements of Purified Wildtype and Mutant CFTR Protein
09:59

Functional Reconstitution and Channel Activity Measurements of Purified Wildtype and Mutant CFTR Protein

Published on: March 9, 2015

12.3K

Phosphodiesterase 8A Regulates CFTR Activity in Airway Epithelial Cells

Mark J Turner1,2, Yukiko Sato3,2, David Y Thomas2,4

  • 1Department of Physiology, McGill University, Montréal, QC, Canada, mark.turner2@mcgill.ca.

Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology
|December 22, 2021
PubMed
Abstract

Insights

Inhibiting phosphodiesterase 8A (PDE8A) increases cyclic AMP (cAMP) levels, enhancing cystic fibrosis transmembrane conductance regulator (CFTR) function. This finding suggests PDE8A is a potential therapeutic target for cystic fibrosis (CF) treatment.

Area of Science:

  • Cellular and Molecular Biology
  • Respiratory Medicine
  • Pharmacology

Background:

  • Cystic fibrosis transmembrane conductance regulator (CFTR) activity is regulated by cyclic AMP (cAMP) and protein kinase A (PKA).
  • Phosphodiesterases (PDEs) modulate intracellular cAMP levels, with PDE8A highly expressed in bronchial epithelial cells.
  • The role of PDE8A in regulating CFTR function in cystic fibrosis (CF) remains largely uncharacterized.

Purpose of the Study:

  • To investigate the role of phosphodiesterase 8A (PDE8A) in the regulation of cystic fibrosis transmembrane conductance regulator (CFTR) activity in primary human bronchial epithelial (pHBE) cells.
  • To assess the impact of PDE8A inhibition on intracellular cAMP levels and CFTR-mediated ion transport in both healthy and CF cells.

Main Methods:

  • Utilized a selective PDE8 inhibitor (PF-04957325) to assess its effects on intracellular cAMP levels ([cAMP]i) in well-differentiated pHBE cells and CFBE41o- WT cells.
  • Measured CFTR channel function using electrophysiological recordings in Ussing chambers.
  • Employed CRISPR Cas9 for PDE8A knockdown and assessed CFTR expression and function.

Main Results:

  • PDE8 inhibition significantly increased intracellular cAMP levels and stimulated wild-type CFTR-dependent ion transport in pHBE cells.
  • PDE8 inhibition showed a synergistic effect with PDE4 inhibition and a greater impact than PDE3 or PDE5 inhibition.
  • CRISPR-mediated PDE8A knockdown affected CFTR expression and the response to PDE8 inhibition. Pharmacological PDE8 inhibition enhanced CFTR activity in CF cells treated with CFTR modulators.

Conclusions:

  • This study provides the first evidence that PDE8A plays a regulatory role in CFTR function.
  • PDE8A is identified as a potential therapeutic target for adjunct therapies aimed at treating cystic fibrosis (CF).
Keywords:
CFTR; Cyclic nucleotide phosphodiesterases; Cystic fibrosis; cAMP signalling

More Related Videos

In Vitro Analysis of PDZ-dependent CFTR Macromolecular Signaling Complexes10:05

In Vitro Analysis of PDZ-dependent CFTR Macromolecular Signaling Complexes

Published on: August 13, 2012

11.5K
Nasal Potential Difference to Quantify Trans-epithelial Ion Transport in Mice08:55

Nasal Potential Difference to Quantify Trans-epithelial Ion Transport in Mice

Published on: July 4, 2018

7.9K

Related Concept Videos

Cystic Fibrosis: Pathogenesis01:23

Cystic Fibrosis: Pathogenesis

Cystic fibrosis (CF), an autosomal recessive disorder, significantly affects the function of exocrine glands. This genetically inherited disease is characterized by the production of thick and sticky mucus, which can severely affect various organs and systems in the body.
CF is primarily caused by a genetic mutation in a chromosome 7 gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most common gene mutation leading to CF is the ΔF508 mutation,...
393
Cystic Fibrosis: Management01:24

Cystic Fibrosis: Management

Cystic fibrosis (CF) is an autosomal recessive disorder that predominantly affects individuals of Northern European descent, occurring at a rate of 1 in 3500. It is caused by a genetic mutation in a gene on chromosome 7, most commonly the ΔF508 mutation, that codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. This results in thicker mucus secretions and obstruction pathologies in multiple organs, including the lungs and sinuses.
Sinus disease and chronic...
238
GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
6.1K
pH Regulation in Cells01:28

pH Regulation in Cells

pH plays a critical role in maintaining normal cellular activities. It helps maintain the structure and function of various proteins, dictates the charge on cellular membranes, and is crucial for metabolic reactions inside the cell. Moreover, cells use the energy from the proton motive force to generate ATP.
Cytosolic pH
Under physiological conditions, the cytosolic pH is slightly more acidic than the extracellular pH. However, cells must prevent further acidification of their cytosol to...
6.8K
Phosphoinositides and PIPs01:42

Phosphoinositides and PIPs

Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
8.9K
Transducer Mechanism: Enzyme-Linked Receptors01:27

Transducer Mechanism: Enzyme-Linked Receptors

Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
3.1K