Molecular mechanism of product storage and release in mucin secretion. II. The role of extracellular Ca++

Verdugo, Pedro; Aitken, Moira L.; Langley, L.; Villalón, Manuel

doi:10.3233/bir-1987-24615

Cited by 80 publications

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“…It is also known that a slight increase of extracellular calcium can drastically slow down swelling of newly released goblet cell granules (17), suggesting that Ca/Na exchange could modulate mucin expansion playing an important role in controlling the rheological properties of mucus (1). However, in a randomly entangled granular mucin, the sole existence of a Donnan drive would not necessarily guarantee its rapid isotropic expansion upon granule release, and it is this fact that supports the necessity of the high mucin organization proposed here.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, the cigar-like structure that can often be observed for the packaged VWF is never observed for mucin storage granules, which are always close to spherical in shape. The work of Verdugo et al (17,18) on the unpacking and secretion of mucins indicates that upon release in exocytosis, these molecules can unfold themselves with great rapidity. This secretion process, which requires the exchange of calcium with sodium, suggests that there must be both ready access to the changing cations and also an ability for the packaged protein not only to change its ionic composition but also expand the whole granule structure uniformly in time rather than stepwise from the granule surface edge.…”

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confidence: 99%

“…This secretion process, which requires the exchange of calcium with sodium, suggests that there must be both ready access to the changing cations and also an ability for the packaged protein not only to change its ionic composition but also expand the whole granule structure uniformly in time rather than stepwise from the granule surface edge. In considering the mucin as a polymer, Verdugo et al (17) have suggested that mucins in the granule matrix must be folded in a non-random conformation. Polarized microscopy images of partially hydrated mucus granules demonstrate that even at visible wavelengths, it is possible to observe the signature of nematic crystalline structures in mucus, which reveals the presence of large-scale supramolecular organization (19).…”

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confidence: 99%

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Unpacking a gel-forming mucin: a view of MUC5B organization after granular release

Kesımer¹,

Makhov

Griffith

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

125

148

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Kesimer M, Makhov AM, Griffith JD, Verdugo P, Sheehan JK. Unpacking a gel-forming mucin: a view of MUC5B organization after granular release. Am J Physiol Lung Cell Mol Physiol 298: L15-L22, 2010. First published September 25, 2009 doi:10.1152/ajplung.00194.2009.-Gel-forming mucins are the largest complex glycoprotein macromolecules in the body. They form the matrix of gels protecting all the surface epithelia and are secreted as disulfide-bonded polymeric structures. The mechanisms by which they are formed and organized within cells and thereafter released to form mucus gels are not understood. In particular, the initial rate of expansion of the mucins after release from their secretory granules is very rapid (seconds), but no clear mechanism for how it is achieved has emerged. Our major interest is in lung mucins, but most particularly in MUC5B, which is the major gel-forming mucin in mucus, and which provides its major protective matrix. In this study, using OptiPrep density gradient ultracentrifugation, we have isolated a small amount of a stable form of the recently secreted and expanding MUC5B mucin, which accounts for less than 2% of the total mucin present. It has an average mass of ϳ150 ϫ 10 6 Da and size Rg of 150 nm in radius of gyration. In transmission electron microscopy, this compact mucin has maintained a circular structure that is characterized by flexible chains connected around protein-rich nodes as determined by their ability to bind colloidal gold. The appearance indicates that the assembled mucins in a single granular form are organized around a number of nodes, each attached to four to eight subunits. The organization of the mucins in this manner is consistent with efficient packing of a number of large heavily glycosylated monomers while still permitting their rapid unfolding and hydration. For the first time, this provides some insight into how the carbohydrate regions might be organized around the NH2-and COOH-terminal globular protein domains within the granule and also explains how the mucin can expand so rapidly upon its release. mucin granule; secretion; mucus MUCINS ARE LARGE COMPLEX GLYCOPROTEIN macromolecules that provide the basis of gels protecting the surface epithelia in many multicellular organisms. In humans, these macromolecules come in two major kinds, the epithelial or transmembrane mucins characterized by COOH-terminal domains that attach to cell surface membranes (5) and those termed the gel-forming mucins that are secreted as highly assembled polymeric structures (14). There are four such molecules, MUC2, MUC5AC, MUC5B, and MUC6, and they form the largest glycoproteins in the body (10). The functions of these molecules are understood in general terms, i.e., they form the basic infrastructure of the epithelial protective gels, but the mechanisms by which they are made and organized within cells and thereafter released are not understood.The basis of the polymeric assembly of these large mucin glycoproteins is thought to mimic that of another related glycoprotein calle...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Unpacking a gel-forming mucin: a view of MUC5B organization after granular release

Kesımer¹,

Makhov

Griffith

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

125

148

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“…Various ion transport imbalances have been associated with CF pathology (8,24,25,38,52). Several cation-centered models (Na ϩ , Ca 2ϩ , and H ϩ ) have been proposed to explain the pathogenic mucus (3,24,27,48). Tangled Ca 2ϩ -crosslinked polyanionic polymer networks, like the matrix of mucus, exhibit unique Na ϩ /Ca 2ϩ ion exchange properties that can drastically control mucus swelling equilibrium (16,48,49) and thereby the viscoelastic properties and rheology of the mucus gel (14,46).…”

mentioning

confidence: 99%

“…Several cation-centered models (Na ϩ , Ca 2ϩ , and H ϩ ) have been proposed to explain the pathogenic mucus (3,24,27,48). Tangled Ca 2ϩ -crosslinked polyanionic polymer networks, like the matrix of mucus, exhibit unique Na ϩ /Ca 2ϩ ion exchange properties that can drastically control mucus swelling equilibrium (16,48,49) and thereby the viscoelastic properties and rheology of the mucus gel (14,46). Thus abnormal fluid absorption, failure to reabsorb or chelate Ca 2ϩ , and low pH have been proposed to interfere with mucus swelling, leading to defective mucus associated with CF (3,24,27,48).…”

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confidence: 99%

A new role for bicarbonate in mucus formation

Chen

Yang

Quinton

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

147

141

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The impact of small anions on the physical properties of gel-forming mucin has been almost overlooked relative to that of cations. Recently, based on the coincident abnormalities in HCO 3 Ϫ secretion and abnormal mucus formed in the hereditary disease cystic fibrosis (CF), HCO 3 Ϫ was hypothesized to be critical in the formation of normal mucus by virtue of its ability to sequester Ca 2ϩ from condensed mucins being discharged from cells.

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The Gallbladder of the Electric Ray Torpedo Marmorata Risso Displays Excrescent Cholecystocytes with Merocrine and Apocrine‐Like Secretions

Gilloteaux

Ott

Oldham-Ott

2012

The Anatomical Record

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The gallbladder of Torpedo marmorata exhibits a mucosal surface layer of simple columnar epithelium with very tall cholecystocytes. The apical domain of each cell has few microvilli, but many mucous vesicles that are secreted by exocytosis at the cell apices. The apical regions may also elongate and undergo self-excision while shedding mucus and cell debris into the gallbladder lumen in a manner similar to that described in mammals as a result of sex steroid treatment to induce gallstones and to that found in the cholecystitis associated with cholelithiasis. Numerous small mitochondria, spherical to elongated, are distributed throughout the cells, while the nuclei are often located in the lower third of each cell. In the lower part of the cholecystocytes, large and very densely contrasted lysosomes can be found. All cells are tightly joined by junctional complexes, including long, highly contrasted desmosomes. The fibromuscular layer is made of a loose stroma with a limited muscular component and a poor blood supply. Large diameter blood vessels can only be found in the subserosal layer. It is hypothesized that the obligatorily carnivorous diet of this ureotelic fish has resulted in the evolution of a gallbladder ultrastructure resembling that found in cholecystitis but without the associated cholelithiasis. Anat Rec,

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Molecular mechanism of product storage and release in mucin secretion. II. The role of extracellular Ca++

Cited by 80 publications

References 0 publications

Unpacking a gel-forming mucin: a view of MUC5B organization after granular release

Unpacking a gel-forming mucin: a view of MUC5B organization after granular release

A new role for bicarbonate in mucus formation

The Gallbladder of the Electric Ray Torpedo Marmorata Risso Displays Excrescent Cholecystocytes with Merocrine and Apocrine‐Like Secretions

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