Lubiprostone Targets Prostanoid Signaling and Promotes Ion Transporter Trafficking, Mucus Exocytosis, and Contractility

• Published in: Digestive diseases and sciences Vol. 57; no. 11; pp. 2826 - 2845
• Main Authors: Jakab, Robert L., Collaco, Anne M., Ameen, Nadia A.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01-11-2012; Springer; Springer Nature B.V
• Subjects: Adenosine triphosphatase; Alprostadil - analogs & derivatives; Alprostadil - pharmacology; Analysis of Variance; Animals; Antiporters - metabolism; Biochemistry; Biopsy; Cyclic AMP-Dependent Protein Kinases - metabolism; Cystic fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Exocytosis - drug effects; Fluorescence; Fluorescent Antibody Technique; Gastroenterology; Hepatology; Humans; In Vitro Techniques; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Ion Transport; Lubiprostone; Medical colleges; Medicine; Medicine & Public Health; Membrane Transport Proteins - metabolism; Mucus - drug effects; Mucus - metabolism; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Muscle, Smooth - metabolism; Oncology; Organic Anion Transporters - metabolism; Original Article; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin E, EP1 Subtype - metabolism; Receptors, Prostaglandin E, EP4 Subtype - metabolism; RNA-Binding Proteins - metabolism; Sodium-Bicarbonate Symporters - metabolism; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers - metabolism; Sodium-Potassium-Chloride Symporters - metabolism; Sodium-Potassium-Exchanging ATPase - metabolism; Transplant Surgery; Receptor signaling; Cystic fibrosis conductance regulator; Membrane trafficking; Ion transporters
• ISSN: 0163-2116; 1573-2568
• DOI: 10.1007/s10620-012-2352-8

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.