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Published ahead of print on July 1, 2004, doi:10.1165/rcmb.2003-0211OC

Am. J. Respir. Cell Mol. Biol., Volume 31, Number 4, October 2004, 446-455

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Submitted on June 10, 2003
Revised on June 29, 2004

Nucleotide-mediated mucin secretion from differentiated human bronchial epithelial cells

Philip A Kemp1, Rosemary A Sugar1, and Alan D Jackson1*

1 Department of Biology III, Novartis Respiratory Research Centre, Horsham, West Sussex, United Kingdom

* To whom correspondence should be addressed. E-mail: alan.jackson{at}pharma.novartis.com.

Most current cell based models for examining the regulation of mucin secretion demonstrate low signal to noise ratios making experimental manipulation and data interpretation difficult. Using ATP as a mucin secretagogue we have developed a model of agonist-induced mucin secretion in differentiated human bronchial epithelial cells (HBECs). Mucin secretory signals were estimated using enzyme-linked lectin assay (ELLA) and typical signals of 300-400% of baseline were observed in response to a 30 minute exposure to ATP (100µM). ATP and UTP equipotently stimulated mucin secretion consistent with mediation via P2Y2 receptor activation. Suramin and AR-C118925XX, a competitive P2Y2 receptor antagonist, inhibited ATP-{gamma}S-induced mucin secretion. A selective Gq G-protein antagonist (GP-ANT-2A) completely abrogated ATP-{gamma}S-induced mucin secretion. Pertussis toxin (PTX) and a Gi/o specific G-protein antagonist (GP-ANT-2) had no effect. The phospholipase C (PLC) inhibitor D609 and the protein kinase C (PKC) inhibitor Calphostin C, substantially inhibited ATP-{gamma}S-induced mucin secretion. PMA also stimulated mucin secretion in a Calphostin C sensitive manner. ATP-{gamma}S-induced mucin secretion was inhibited by the Ca2+-chelator ((1,2-bis(o-aminophenoxy) ethane-N,N,N',N'-tetra-acetic acid tetra (acetoxymethyl) ester)) (BAPTA-AM). Ionomycin and thapsigargin both stimulated mucin secretion. Our data are broadly consistent with known G-protein coupling and down-stream signalling events associated with the P2Y2 receptor. The exceptional signal to noise ratios obtained using this model have permitted clear evaluation of the involvement of these mechanisms in agonist-induced mucin secretion from differentiated HBECs.




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