Regulation of mucin secretion from in vitro cellular models.
Conceptually, in vitro models for airway mucin secretion may provide useful information pertinent to many aspects of goblet cell biology/physiology. Such models may be especially useful in identifying potential secretagogues, probing the distribution of receptors between goblet cell apical and basolateral membrane domains, and revealing intracellular messenger pathways underlying receptor activation. We have focused most recently on human bronchial epithelial cell cultures grown as tracheal xenografts and SPOC1 cell cultures. These two models are remarkably similar with respect to the regulation of mucin secretion: luminal challenges with the P2Y2 purinoceptor agonists ATP or UTP elicit mucin secretion with EC50s of about 3 microM and archetypal agonists to other purinoceptors test negative. P2Y2 purinoceptors typically couple via Gq to phospholipase C, suggesting that intracellular Ca2+ and protein kinase C (PKC) are important in activating intracellular pathways leading to goblet cell mucin release. Consistent with this notion, phorbol myristate acetate and ionomycin elicit mucin secretion from SPOC1 cells and HBE xenografts, whereas cyclic nucleotides do not. Delineation of the molecules comprising these receptor/messenger interactions and their supporting pathways remains an important challenge for the development of drugs effective in therapeutic interventions in mucin hypersecretory airway diseases; with these models we have initiated the process.
Davis
C William
CW
Department of Cell and Molecular Physiology, and Cystic Fibrosis/Pulmonary Research and Treatment Center, 6009 Thurston-Bowles, University of North Carolina, Chapel Hill, NC 27599-7248, USA.
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001485:Basement Membrane / Q000502:physiology; D001980:Bronchi / Q000166:cytology; D020013:Calcium Signaling; D016764:Cell Polarity; D002478:Cells, Cultured; D002645:Chickens; D005088:Exocrine Glands / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020397:Goblet Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D015759:Ionomycin / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009077:Mucins / Q000378:metabolism*; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2 / Q000502:physiology; D058473:Receptors, Purinergic P2Y2; D012636:Secretory Rate / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014132:Trachea / Q000637:transplantation; D014183:Transplantation, Heterologous; D016042:Transplantation, Heterotopic; D014544:Uridine Triphosphate / Q000494:pharmacology
D009077:Mucins; C546385:P2RY2 protein, human; C546386:P2ry2 protein, mouse; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; D015759:Ionomycin; D000255:Adenosine Triphosphate; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins; D013755:Tetradecanoylphorbol Acetate; D014544:Uridine Triphosphate