Lubiprostone targets prostanoid EP₄ receptors in ovine airways.
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Journal: 2011/June - British Journal of Pharmacology
ISSN: 1476-5381
Abstract:
OBJECTIVE
Lubiprostone, a prostaglandin E₁ derivative, is reported to activate ClC-2 chloride channels located in the apical membranes of a number of transporting epithelia. Lack of functioning CFTR chloride channels in epithelia is responsible for the genetic disease cystic fibrosis, therefore, surrogate channels that can operate independently of CFTR are of interest. This study explores the target receptor(s) for lubiprostone in airway epithelium.
METHODS
All experiments were performed on the ventral tracheal epithelium of sheep. Epithelia were used to measure anion secretion from the apical surface as short circuit current or as fluid secretion from individual airway submucosal glands, using an optical method.
RESULTS
The EP₄ antagonists L-161982 and GW627368 inhibited short circuit current responses to lubiprostone, while EP₁(,)₂(&)₃ receptor antagonists were without effect. Similarly, lubiprostone induced secretion in airway submucosal glands was inhibited by L-161982. L-161982 effectively competed with lubiprostone with a K(d) value of 0.058 µM, close to its value for binding to human EP₄ receptors (0.024 µM). The selective EP₄ agonist L-902688 and lubiprostone behaved similarly with respect to EP₄ receptor antagonists. Results of experiments with H89, a protein kinase A inhibitor, were consistent with lubiprostone acting through a G(s) -protein coupled EP₄ receptor/cAMP cascade.
CONCLUSIONS
Lubiprostone-induced short-circuit currents and submucosal gland secretions were inhibited by selective EP₄ receptor antagonists. The results suggest EP₄ receptor activation by lubiprostone triggers cAMP production necessary for CFTR activation and the secretory responses, a possibility precluded in CF tissues.
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Br J Pharmacol 162(2): 508-520
PMID: 20883477

Lubiprostone targets prostanoid EP<sub>4</sub> receptors in ovine airways

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Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
AW Cuthbert, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. E-mail: ku.ca.mac@0001cwa
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
Received 2010 Jun 2; Revised 2010 Aug 31; Accepted 2010 Sep 2.
Copyright British Journal of Pharmacology © 2011 The British Pharmacological Society

Abstract

BACKGROUND AND PURPOSE

Lubiprostone, a prostaglandin E1 derivative, is reported to activate ClC-2 chloride channels located in the apical membranes of a number of transporting epithelia. Lack of functioning CFTR chloride channels in epithelia is responsible for the genetic disease cystic fibrosis, therefore, surrogate channels that can operate independently of CFTR are of interest. This study explores the target receptor(s) for lubiprostone in airway epithelium.

EXPERIMENTAL APPROACH

All experiments were performed on the ventral tracheal epithelium of sheep. Epithelia were used to measure anion secretion from the apical surface as short circuit current or as fluid secretion from individual airway submucosal glands, using an optical method.

KEY RESULTS

The EP4 antagonists L-161982 and {"type":"entrez-nucleotide","attrs":{"text":"GW627368","term_id":"290498219","term_text":"GW627368"}}GW627368 inhibited short circuit current responses to lubiprostone, while EP1,2&amp;3 receptor antagonists were without effect. Similarly, lubiprostone induced secretion in airway submucosal glands was inhibited by L-161982. L-161982 effectively competed with lubiprostone with a Kd value of 0.058 µM, close to its value for binding to human EP4 receptors (0.024 µM). The selective EP4 agonist L-902688 and lubiprostone behaved similarly with respect to EP4 receptor antagonists. Results of experiments with H89, a protein kinase A inhibitor, were consistent with lubiprostone acting through a Gs-protein coupled EP4 receptor/cAMP cascade.

CONCLUSIONS AND IMPLICATIONS

Lubiprostone-induced short-circuit currents and submucosal gland secretions were inhibited by selective EP4 receptor antagonists. The results suggest EP4 receptor activation by lubiprostone triggers cAMP production necessary for CFTR activation and the secretory responses, a possibility precluded in CF tissues.

Keywords: airway anion secretion, airway submucosal glands, selective EP4 agonists and antagonists, CFTR, ClC-2 chloride channels
Abstract

Acknowledgments

Support from the Cystic Fibrosis Trust is gratefully acknowledged.

Acknowledgments

Glossary

Abbreviations

AH 68096-isopropoxy-9-oxoxanthene-2-carboxylic acid
apapical
ASLairway surface liquid
blbasolateral
CFTRcystic fibrosis transmembrane conductance regulator
GW627368X((N-{2-[4-(4,49-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetyl}benzene sulphonamide)
KHSKrebs-Henseleit solution
L-161982N-[[4'-[[3-butyl-1,5-dihydro-5-oxo-1-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-4-yl]methyl][1,1'-biphenyl]-2yl]-3-methyl-2-thiophenecarboxamide
L-9026885R-[(1E)-4,4-difluoro-3R-hydroxy-4-phenylbut-1-en-1-1-yl]-1-[6-(1H-tetrazol-5-yl)hexyl]pyrrolidin-2-one
SC-192201-acetyl-2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydrazine
SCCshort circuit current
Glossary
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