Nobiletin Stimulates Chloride Secretion in Human Bronchial Epithelia via a cAMP/PKA-Dependent Pathway.

Abstract

BACKGROUND/AIMS:

Nobiletin, a citrus flavonoid isolated from tangerines, alters ion transport functions in intestinal epithelia, and has antagonistic effects on eosinophilic airway inflammation of asthmatic rats. The present study examined the effects of nobiletin on basal short-circuit current (I(SC)) in a human bronchial epithelial cell line (16HBE14o-), and characterized the signal transduction pathways that allowed nobiletin to regulate electrolyte transport.

METHODS:

The I(SC) measurement technique was used for transepithelial electrical measurements. Intracellular calcium ([Ca(2+)]i) and cAMP were also quantified.

RESULTS:

Nobiletin stimulated a concentration-dependent increase in I(SC), which was due to Cl- secretion. The increase in I(SC) was inhibited by a cystic fibrosis transmembrane conductance regulator inhibitor (CFTR(inh)-172), but not by 4,4'-diisothiocyano-stilbene-2,2'-disulphonic acid (DIDS), Chromanol 293B, clotrimazole, or TRAM-34. Nobiletin-stimulated I(SC) was also sensitive to a protein kinase A (PKA) inhibitor, H89, and an adenylate cyclase inhibitor, MDL-12330A. Nobiletin could not stimulate any increase in I(SC) in a cystic fibrosis (CF) cell line, CFBE41o-, which lacked a functional CFTR. Nobiletin stimulated a real-time increase in cAMP, but not [Ca(2+)]i.

CONCLUSION:

Nobiletin stimulated transepithelial Cl- secretion across human bronchial epithelia. The mechanisms involved activation of adenylate cyclase- and cAMP/PKA-dependent pathways, leading to activation of apical CFTR Cl- channels.

• Authors: Yuan Hao, Cindy S T Cheung, Wallace C Y Yip, Wing-hung Ko
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 37 Issue 1 Pg. 306-20 ( 2015) ISSN: 1421-9778 [Electronic] Germany
• PMID: 26316078 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 S. Karger AG, Basel.

Chemical References

• Chlorides
• Flavones
• Imines
• Isoquinolines
• Sulfonamides
• Cystic Fibrosis Transmembrane Conductance Regulator
• RMI 12330A
• nobiletin
• Cyclic AMP
• Cyclic AMP-Dependent Protein Kinases
• Adenylyl Cyclases
• N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
• Calcium

Topics

• Adenylyl Cyclases (metabolism)
• Bronchi (drug effects, metabolism)
• Calcium (metabolism)
• Cell Line
• Chlorides (metabolism)
• Cyclic AMP (metabolism)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Cystic Fibrosis (metabolism)
• Cystic Fibrosis Transmembrane Conductance Regulator (metabolism)
• Epithelial Cells (drug effects, metabolism)
• Flavones (pharmacology)
• Humans
• Imines (pharmacology)
• Ion Transport (drug effects)
• Isoquinolines (pharmacology)
• Respiratory Mucosa (drug effects, metabolism)
• Signal Transduction (drug effects)
• Sulfonamides (pharmacology)