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Actions of adenosine A1 and A2 receptor antagonists on CFTR antibody-inhibited beta-adrenergic mucin secretion
M M Pereira1, C Lloyd Mills, R L Dormer
1Department of Medical Biochemistry, University of Wales College of Medicine, Heath Park, Cardiff.
Abstract:
1. The cystic fibrosis gene protein, the cystic fibrosis transmembrane conductance regulator (CFTR) acts as a chloride channel and is a key regulator of mucin secretion. The mechanism by which 3-isobutyl-1-methylxanthine (IBMX) corrects the defect in CFTR mediated beta-adrenergic stimulation of mucin secretion has not been determined. The present study has investigated the actions of adenosine A1 and A2 receptor antagonists to determine whether ability to stimulate mucin secretion correlates with correction of CFTR antibody inhibited beta-adrenergic response and whether excessive cyclic AMP rise is required. 2. CFTR antibodies were introduced into living rat submandibular acini by hypotonic swelling. Following recovery, mucin secretion in response to isoproterenol was measured. 3. The adenosine A1 receptor antagonist, 8 cyclopentyltheophylline (CPT) was a less potent stimulator of mucin secretion than was the A2 receptor antagonist dimethylpropargylxanthine (DMPX). A concentration of CPT close to the Ki for A1 receptor antagonism (10 nM) did not stimulate mucin secretion. 4. DMPX, although a potent stimulator of mucin secretion, did not correct CFTR antibody inhibited mucin secretion. 5. CPT corrected defective CFTR antibody inhibited mucin secretion at a high (1 mM) concentration, suggesting a mechanism other than adenosine receptor antagonism. 6. DMPX potentiated the isoproterenol induced cyclic AMP rise, whereas CPT did not. 7. Correction of the defective CFTR mucin secretion response did not correlate with ability to stimulate mucin secretion and did not require potentiation of beta-adrenergic induced increases in cyclic AMP. This affords real promise for the development of a selective drug treatment for cystic fibrosis.
Insights
Cystic fibrosis transmembrane conductance regulator (CFTR) drug development shows promise. Adenosine receptor antagonists were tested for correcting CFTR defects, revealing a potential new therapeutic pathway for cystic fibrosis treatment.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Cystic fibrosis transmembrane conductance regulator (CFTR) protein regulates mucin secretion.
- The mechanism of 3-isobutyl-1-methylxanthine (IBMX) in correcting CFTR defects is unknown.
- This study investigates adenosine receptor antagonists' role in CFTR-mediated mucin secretion.
Purpose of the Study:
- To determine if adenosine A1 and A2 receptor antagonists can correct CFTR antibody-inhibited beta-adrenergic response.
- To investigate if stimulating mucin secretion correlates with correcting CFTR defects.
- To ascertain if excessive cyclic AMP (cAMP) rise is necessary for correcting CFTR defects.
Main Methods:
- Rat submandibular acini were treated with CFTR antibodies via hypotonic swelling.
- Mucin secretion was measured in response to isoproterenol.
- Adenosine A1 (8-cyclopentyltheophylline, CPT) and A2 (dimethylpropargylxanthine, DMPX) receptor antagonists were used.
Main Results:
- CPT corrected CFTR antibody-inhibited mucin secretion at 1 mM, independent of adenosine receptor antagonism.
- DMPX stimulated mucin secretion but did not correct CFTR antibody inhibition.
- CPT did not potentiate isoproterenol-induced cAMP rise, while DMPX did.
Conclusions:
- Correction of defective CFTR mucin secretion does not require potentiation of beta-adrenergic induced cAMP increases.
- The mechanism of CPT in correcting CFTR defects may involve pathways other than adenosine receptor antagonism.
- These findings offer promise for developing selective drug treatments for cystic fibrosis.