Absence of CFTR is associated with pleiotropic effects on mucins in mouse gallbladder epithelial cells

Kuver, Rahul; Wong, Teng-fong; Klinkspoor, J. H.; Lee, Sum P.

doi:10.1152/ajpgi.00547.2005

Cited by 14 publications

(14 citation statements)

References 46 publications

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“…If exposure to a high luminal HCO 3 -concentration can also be regarded as a stimulus of exocytosis, then "swelling" of the granule cluster prior to exocytosis appears to be a consistent feature of stimulated Cftr-KO goblet cells. Preexocytotic granule swelling and delayed exocytosis are consistent with the slow rate of swelling and diffusivity of mucin granules released by Cftr-KO gallbladder columnar cells (54). Further studies will be necessary to determine whether this abnormality results from a defect intrinsic to the stored granule (e.g., improper processing, imbalance in Ca 2+ shielding), an alteration in granule membrane electrolyte transport, or a disruption of secretory pore formation in the Cftr-KO goblet cell.…”

Section: Discussionmentioning

confidence: 67%

Defective goblet cell exocytosis contributes to murine cystic fibrosis–associated intestinal disease

Liu¹,

Walker²,

Ootani³

et al. 2015

J. Clin. Invest.

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Section: Discussionmentioning

confidence: 67%

Defective goblet cell exocytosis contributes to murine cystic fibrosis–associated intestinal disease

Liu¹,

Walker²,

Ootani³

et al. 2015

J. Clin. Invest.

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Section: Figure 11mentioning

confidence: 99%

“…Just as pertinent, the swelling of mucus granules released from CFTR -/-mouse gallbladder cells was substantially slower and their calcium content appreciably higher as compared with WT cells (55). Moreover, it has been recognized, but unexplained, for decades that relatively pure samples of several mucus-containing CF secretions harbor elevated calcium concentrations (55)(56)(57)(58). Interestingly, intestinal crypt mucus and Paneth cell granules (which were found to accumulate in intestinal crypts in CF as does mucus) showed increased clearance and dissolution when CF mice were fed on a diet with HCO 3 --rich polyethylene glycol laxative (59,60).…”

Section: Figure 11mentioning

confidence: 99%

Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator–dependent bicarbonate secretion

García

Yang²,

Quinton³

2009

J. Clin. Invest.

261

239

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The mechanisms underlying mucus-associated pathologies in cystic fibrosis (CF) remain obscure. However, recent studies indicate that CF transmembrane conductance regulator (CFTR) is required for bicarbonate (HCO 3 -) transport and that HCO 3 -is critical for normal mucus formation. We therefore investigated the role of HCO 3 -in mucus secretion using mouse small intestine segments ex vivo. Basal rates of mucus release in the presence or absence of HCO 3 -were similar. However, in the absence of HCO 3 -, mucus release stimulated by either PGE 2 or 5-hydroxytryptamine (5-HT) was approximately half that stimulated by these molecules in the presence of HCO 3 -. Inhibition of HCO 3 -and fluid transport markedly reduced stimulated mucus release. However, neither absence of HCO 3 -nor inhibition of HCO 3 -transport affected fluid secretion rates, indicating that the effect of HCO 3 -removal on mucus release was not due to decreased fluid secretion. In a mouse model of CF (mice homozygous for the most common human CFTR mutation), intestinal mucus release was minimal when stimulated with either PGE 2 or 5-HT in the presence or absence of HCO 3 -. These data suggest that normal mucus release requires concurrent HCO 3 -secretion and that the characteristically aggregated mucus observed in mucin-secreting organs in individuals with CF may be a consequence of defective HCO 3 -transport.

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“…The current paradigm explaining mucin granule organization and biogenesis was originally proposed by the Verdugo laboratory on the basis of video-enhanced microscopy studies that made it possible to visualize and monitor the discharge of mucin granules in cultured mucous cells (14,(33)(34)(35)(36). Thus, upon fusion of the granule with the plasma membrane, the intragranular (mucin) matrix abruptly swelled, discharging the accompanying secretory products.…”

Section: The Matrix Core Paradigmmentioning

confidence: 99%

Mucin Granule Intraluminal Organization

Pérez-Vilar

2007

Am J Respir Cell Mol Biol

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Mucus secretions have played a central role in the evolution of multicellular organisms, enabling adaptation to widely differing environments. In vertebrates, mucus covers and protects the epithelial cells in the respiratory, gastrointestinal, urogenital, visual, and auditory systems, amphibian's epidermis, and the gills in fishes. Deregulation of mucus production and/or composition has important consequences for human health. For example, mucus obstruction of small airways is observed in chronic airway diseases, including chronic obstructive pulmonary disease, asthma, and cystic fibrosis. The major protein component in the mucus is a family of large, disulfide-bonded glycoproteins known as gel-forming mucins. These proteins are accumulated in large, regulated secretory granules (the mucin granules) that occupy most of the apical cytoplasm of specialized cells known as mucous/goblet cells. Since mucin oligomers have contour dimensions larger than the mucin granule average diameter, the question arises how these highly hydrophilic macromolecules are organized within these organelles. I review here the intraluminal organization of the mucin granule in view of our knowledge on the structure, biosynthesis, and biophysical properties of gel-forming mucins, and novel imaging studies in living mucous/goblet cells. The emerging concept is that the mucin granule lumen comprises a partially condensed matrix meshwork embedded in a fluid phase where proteins slowly diffuse.Keywords: granule matrix; mucin granules; mucins; secretory granules; secretion GEL-FORMING MUCINS: STRUCTURE AND BIOSYNTHESISFive gel-forming mucins (MUC2, MUC5AC, MUC5B, MUC6, and MUC19) have been found in humans. These mucins share a similar structural organization ( Figure 1A) characterized by (1, 2): (i ) multi-domain polypeptide chains with thousands of amino acid residues; (ii) a large, centrally located region mainly consisting of threonine and/or serine-rich tandemly repeated sequences to which O-linked oligosaccharides are covalently bound; (iii) the presence of several under-glycosylated, Cys-rich domains that are conserved among different mucins; (iv) the formation of disulfide-linked species ranging from dimers to more than 16 oligomers (3); and (v ) molecular polydispersity because of genetic polymorphism (e.g., multiple alleles encoding

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Absence of CFTR is associated with pleiotropic effects on mucins in mouse gallbladder epithelial cells

Cited by 14 publications

References 46 publications

Defective goblet cell exocytosis contributes to murine cystic fibrosis–associated intestinal disease

Defective goblet cell exocytosis contributes to murine cystic fibrosis–associated intestinal disease

Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator–dependent bicarbonate secretion

Mucin Granule Intraluminal Organization

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