期刊
ANNUAL REVIEW OF PHYSIOLOGY
卷 70, 期 -, 页码 487-512出版社
ANNUAL REVIEWS
DOI: 10.1146/annurev.physiol.70.113006.100638
关键词
secretion; exocytosis; mucus; mucociliary clearance
类别
资金
- NCI NIH HHS [P30CA16672] Funding Source: Medline
- NHLBI NIH HHS [HL063756, HL072984] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [P30CA016672] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL072984, R01HL063756] Funding Source: NIH RePORTER
Major advances in understanding regulated mucin secretion from air-way goblet cells have been made in the past decade in the areas of pharmacology and basic cell biology. For instance, it is now appreciated that nucleotide agonists acting locally through P2Y purinoceptors on apical membranes of surface goblet cells provide the major regulatory system for mucin secretion. Similarly, Clara cells, the primary secretory cell in the mouse air-ways (and human small airways), are now recognized as major mucin-secreting cells. In Clara cells, the relative lack of staining for mucosubstances reflects essentially equal baseline rates of mucin synthesis and secretion, with little to no accumulation of mucin granules in storage pools. During mucous metaplasia induced under inflammatory conditions, mucin synthesis is massively upregulated in Clara cells, and stored mucin granules come to dominate the secretory cell phenotype. More importantly, we have seen a transition in the past fewyears from a pharmacological focus on regulated mucin secretion to a more molecular mechanistic focus that has great promise going forward. In part, these advances are occurring through the use of well-differentiated primary human bronchial epithelial cell cultures, but recent work in mouse models perhaps has had the most important impact. Emerging data from Munc13-2- and synaptotagmin 2-deficient mouse models represent the first direct, molecular-level manipulations of proteins involved in regulated secretory cell mucin secretion. These new data indicatc that Munc13-2 is responsible for regulating a baseline mucin secretory pathway in the airways and is not essential for purinergic agonist-induced mucin secretion. In contrast, synaptotagmin 2, a fast Ca2+ sensor for the SNARE complex, is essential for regulated secretion. Interestingly, these early results suggest that there are two pathways for excocytic mucin release from goblet cells.
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