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A(2) adenosine receptors regulate CFTR through PKA and PLA(2)

B R Cobb1, F Ruiz, C M King

  • 1Department of Human Genetics, University of Alabama at Birmingham, 35233, USA.

American Journal of Physiology. Lung Cellular and Molecular Physiology
|December 14, 2001
PubMed

Insights

Adenosine (Ado) activates cystic fibrosis transmembrane conductance regulator (CFTR) via A(2B) receptors, involving phospholipase A(2) (PLA(2)) and protein kinase A. This pathway enhances both wild-type and mutant CFTR activity.

Area of Science:

  • Cell Biology
  • Molecular Physiology
  • Respiratory Medicine

Background:

  • Adenosine (Ado) is a key signaling molecule in various physiological processes.
  • The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel implicated in cystic fibrosis.
  • Understanding CFTR regulation is vital for developing novel therapeutic strategies.

Purpose of the Study:

  • To investigate the role of adenosine (Ado) in activating the cystic fibrosis transmembrane conductance regulator (CFTR).
  • To elucidate the specific signaling pathways involved in Ado-mediated CFTR activation, including receptors and enzymes.
  • To assess the potential of this pathway to modulate both wild-type and mutant CFTR function.

Main Methods:

  • In vitro studies using various cell lines (Calu-3, IB-3-1, COS-7) and primary human airway cells.
  • In vivo experiments utilizing wild-type and CFTR-deficient mice.
  • Measurement of intracellular cAMP levels, halide efflux, and arachidonic acid release.
  • Pharmacological inhibition of specific receptors (A(2B)) and enzymes (PLA(2), cPLA(2)).
  • Expression studies involving wild-type, DeltaF508, and G551D mutant CFTR.

Main Results:

  • A(2B) adenosine receptors were identified in airway cells and mediated Ado-induced cAMP elevation and protein kinase A-dependent halide efflux.
  • Adenosine stimulated arachidonic acid release, and phospholipase A(2) (PLA(2)) inhibition blocked Ado-activated halide efflux, indicating PLA(2) involvement.
  • Ado stimulated CFTR-dependent nasal chloride secretion in mice, sensitive to A(2) receptor and PLA(2) blockade.
  • Adenosine activated halide efflux in cells expressing both wild-type and mutant CFTR (DeltaF508, G551D), with the latter requiring additional factors.

Conclusions:

  • Phospholipase A(2) (PLA(2)) and protein kinase A (PKA) are essential components of A(2B) receptor-mediated activation of CFTR.
  • This signaling pathway can enhance the activity of both wild-type and mutant forms of CFTR.
  • Targeting this adenosine-mediated pathway presents a potential therapeutic avenue for cystic fibrosis and other CFTR-related disorders.

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