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Increased expression of G protein-coupled receptor kinases in cystic fibrosis lung

Judith C W Mak1, Tsu Tshen Chuang, Carol A Harris

  • 1Department of Thoracic Medicine, National Heart and Lung Institute, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Dovehouse Street, London SW3 6LY, UK. j.mak@ic.ac.uk

European Journal of Pharmacology
|February 23, 2002
PubMed

Insights

Increased G protein-coupled receptor kinase (GRK) activity in cystic fibrosis lung may explain reduced beta2-adrenoceptor density. This points to GRK as a key factor in cystic fibrosis airway dysfunction.

Area of Science:

  • Pulmonary Medicine
  • Molecular Biology
  • Pharmacology

Background:

  • Reduced airway beta-adrenoceptor density is observed in cystic fibrosis (CF) lungs.
  • The underlying mechanisms for this beta-adrenoceptor downregulation in CF remain poorly understood.

Purpose of the Study:

  • To investigate the association between decreased beta2-adrenoceptor density and altered G protein-coupled receptor kinase (GRK) levels in cystic fibrosis lung.
  • To elucidate the role of GRK in the pathophysiology of CF airways.

Main Methods:

  • Assessed GRK activity via rhodopsin phosphorylation in lung homogenates.
  • Quantified beta2-adrenoceptor and GRK mRNA and protein levels using Northern and Western blotting.
  • Compared peripheral lung samples from normal donors and cystic fibrosis patients.

Main Results:

  • Significantly increased GRK activity was observed in cystic fibrosis lung tissue.
  • Parallel increases in GRK2 and GRK5 mRNA and protein expression were detected in CF lungs.
  • Isoproterenol-stimulated adenylyl cyclase activity was reduced by 65% in cystic fibrosis lung homogenates.

Conclusions:

  • Elevated GRK activity is a potential mechanism contributing to altered beta2-adrenoceptor and adenylyl cyclase coupling in cystic fibrosis.
  • Increased GRK activity may play a role in the downregulation of beta2-adrenoceptors in the CF lung, impacting airway function.

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