Digestive Diseases and Sciences

, Volume 57, Issue 11, pp 2826–2845

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

  • Robert L. Jakab
  • Anne M. Collaco
  • Nadia A. Ameen
Original Article

DOI: 10.1007/s10620-012-2352-8

Cite this article as:
Jakab, R.L., Collaco, A.M. & Ameen, N.A. Dig Dis Sci (2012) 57: 2826. doi:10.1007/s10620-012-2352-8
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Abstract

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), Ca2+ 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.

Keywords

Ion transporters Membrane trafficking Receptor signaling Cystic fibrosis conductance regulator 

Supplementary material

10620_2012_2352_MOESM1_ESM.doc (64 kb)
Supplementary material 1 (DOC 64 kb)

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Robert L. Jakab
    • 1
  • Anne M. Collaco
    • 1
  • Nadia A. Ameen
    • 1
    • 2
  1. 1.Department of Pediatrics/Gastroenterology and HepatologyYale University School of MedicineNew HavenUSA
  2. 2.Department of Cellular and Molecular PhysiologyYale University School of MedicineNew HavenUSA