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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Regulation of adherens junctions and epithelial paracellular permeability: a novel function for polyamines

Departments of ¹Surgery and ²Pathology, University of Maryland School of Medicine, and ³Baltimore Department of Veterans Affairs Medical Center, Baltimore, Maryland 21201

Submitted 13 January 2003 ; accepted in final form 7 July 2003

Maintenance of intestinal mucosal epithelial integrity requires polyamines that are involved in the multiple signaling pathways controlling gene expression and different epithelial cell functions. Integrity of the intestinal epithelial barrier depends on a complex of proteins composing different intercellular junctions, including tight junctions, adherens junctions, and desmosomes. E-cadherin is primarily found at the adherens junctions and plays a critical role in cell-cell adhesions that are fundamental to formation of the intestinal epithelial barrier. The current study determined whether polyamines regulate intestinal epithelial barrier function by altering E-cadherin expression. Depletion of cellular polyamines by -difluoromethylornithine (DFMO) reduced intracellular free Ca²⁺ concentration ([Ca²⁺]_cyt), decreased E-cadherin expression, and increased paracellular permeability in normal intestinal epithelial cells (IEC-6 line). Polyamine depletion did not alter expression of tight junction proteins such as zona occludens (ZO)-1, ZO-2, and junctional adhesion molecule (JAM)-1. Addition of exogenous polyamine spermidine reversed the effects of DFMO on [Ca²⁺]_cyt and E-cadherin expression and restored paracellular permeability to near normal. Elevation of [Ca²⁺]_cyt by the Ca²⁺ ionophore ionomycin increased E-cadherin expression in polyamine-deficient cells. In contrast, reduction of [Ca²⁺]_cyt by polyamine depletion or removal of extracellular Ca²⁺ not only inhibited expression of E-cadherin mRNA but also decreased the half-life of E-cadherin protein. These results indicate that polyamines regulate intestinal epithelial paracellular barrier function by altering E-cadherin expression and that polyamines are essential for E-cadherin expression at least partially through [Ca²⁺]_cyt.

ornithine decarboxylase; tight junction; catenins; intracellular calcium; normal intestinal epithelial cells

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