Document Detail


Lubiprostone targets prostanoid signaling and promotes ion transporter trafficking, mucus exocytosis, and contractility.
MedLine Citation:
PMID:  22923315     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND AIM: Lubiprostone is a chloride channel activator in clinical use for the treatment of chronic constipation, but the mechanisms of action of the drug are poorly understood. The aim of this study was to determine whether lubiprostone exerts secretory effects in the intestine by membrane trafficking of ion transporters and associated machinery.
METHODS: Immunolabeling and quantitative fluorescence intensity were used to examine lubiprostone-induced trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR), sodium/potassium-coupled chloride co-transporter 1 (NKCC1), electrogenic sodium/bicarbonate co-transporter 1 (NBCe1), down-regulated in adenoma (DRA), putative anion transporter 1 (PAT1), sodium/proton exchanger 3 (NHE3), Ca(2+) activated chloride channel 2 (ClC-2) serotonin and its transporter SERT, E prostanoid receptors EP4 and EP1, sodium/potassium ATPase (Na-K-ATPase) and protein kinase A (PKA). The effects of lubiprostone on mucus exocytosis in rat intestine and human rectosigmoid explants were also examined.
RESULTS: Lubiprostone induced contraction of villi and proximal colonic plicae and membrane trafficking of transporters that was more pronounced in villus/surface cells compared to the crypt. Membrane trafficking was determined by: (1) increased membrane labeling for CFTR, PAT1, NKCC1, and NBCe1 and decreased membrane labeling for NHE3, DRA and ClC-2; (2) increased serotonin, SERT, EP4, EP1 and PKA labeling in enterochromaffin cells; (3) increased SERT, EP4, EP1, PKA and Na-K-ATPase in enterocytes; and (4) increased mucus exocytosis in goblet cells.
CONCLUSION: These data suggest that lubiprostone can target serotonergic, EP4/PKA and EP1 signaling in surface/villus regions; stimulate membrane trafficking of CFTR/NBCe1/NKCC1 in villus epithelia and PAT1/NBCe1/NKCC1 in colonic surface epithelia; suppress NHE3/DRA trafficking and fluid absorption; and enhance mucus-mobilization and mucosal contractility.
Authors:
Robert L Jakab; Anne M Collaco; Nadia A Ameen
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-08-25
Journal Detail:
Title:  Digestive diseases and sciences     Volume:  57     ISSN:  1573-2568     ISO Abbreviation:  Dig. Dis. Sci.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-16     Completed Date:  2013-01-04     Revised Date:  2013-12-05    
Medline Journal Info:
Nlm Unique ID:  7902782     Medline TA:  Dig Dis Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2826-45     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Alprostadil / analogs & derivatives*,  pharmacology
Analysis of Variance
Animals
Antiporters / metabolism
Biopsy
Cyclic AMP-Dependent Protein Kinases / metabolism
Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
Exocytosis / drug effects*
Fluorescent Antibody Technique
Humans
Intestinal Mucosa / drug effects*,  metabolism*
Ion Transport
Membrane Transport Proteins / metabolism
Mucus / drug effects*,  metabolism*
Muscle Contraction / drug effects*
Muscle, Smooth / drug effects*,  metabolism*
Organic Anion Transporters / metabolism
RNA-Binding Proteins / metabolism
Rats
Rats, Sprague-Dawley
Receptors, Prostaglandin E, EP1 Subtype / metabolism
Receptors, Prostaglandin E, EP4 Subtype / metabolism
Sodium-Bicarbonate Symporters / metabolism
Sodium-Hydrogen Antiporter / metabolism
Sodium-Potassium-Chloride Symporters / metabolism
Sodium-Potassium-Exchanging ATPase / metabolism
Grant Support
ID/Acronym/Agency:
P30 DK 34989/DK/NIDDK NIH HHS; R01 DK 077065/DK/NIDDK NIH HHS; R01 DK077065/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Antiporters; 0/Membrane Transport Proteins; 0/Organic Anion Transporters; 0/RNA-Binding Proteins; 0/Receptors, Prostaglandin E, EP1 Subtype; 0/Receptors, Prostaglandin E, EP4 Subtype; 0/SERT protein, rat; 0/SLC26A6 protein, human; 0/Slc26a3 protein, rat; 0/Slc4a4 protein, rat; 0/Sodium-Bicarbonate Symporters; 0/Sodium-Hydrogen Antiporter; 0/Sodium-Potassium-Chloride Symporters; 0/citrate-isocitrate carrier, rat; 0/sodium-hydrogen exchanger 3; 126880-72-6/Cystic Fibrosis Transmembrane Conductance Regulator; 7662KG2R6K/lubiprostone; EC 2.7.11.11/Cyclic AMP-Dependent Protein Kinases; EC 3.6.3.9/Sodium-Potassium-Exchanging ATPase; F5TD010360/Alprostadil
Comments/Corrections
Comment In:
Dig Dis Sci. 2012 Nov;57(11):2740-2   [PMID:  23001408 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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