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

Abstract

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 alpha-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.

Polyamines and cancer: old molecules, new understanding

“…Experiments in cell culture showed that the effects of the ODC inhibitor could be rescued by exogenous putrescine, supporting the interpretation that these genes are regulated by polyamine-dependent mechanisms. Other groups have observed similar effects of DFMO on cell-junction proteins 51,52 , although alterations seem to be cell-type specific.…”

Epac-Rap Signaling Reduces Cellular Stress and Ischemia-induced Kidney Failure

“…14 Previous studies have demonstrated that adherens junctions stabilization was sufficient to strengthen epithelial barrier function. 35 Our findings using electric cell-substrate impedance sensing (ECIS) suggest that the loss of TER is reduced, but we cannot rule out that this effect on TER may be influenced by Epac-mediated cell spreading affecting the intercellular space in an adhesion-independent fashion. Here we demonstrated that hypoxia-induced loss of focal adhesions is reduced by activation of Epac using paxillin as a functional marker ( Figure 5).…”

Blood–testis barrier dynamics are regulated by an engagement/disengagement mechanism between tight and adherens junctions via peripheral adaptors

“…Nonetheless, these findings fail to explain the necessity of the coexisting TJs and AJs at the BTB that maintains its integrity during spermatogenesis. In two recent studies, it was shown that AJ disruption in the seminiferous epithelium induced by a suppression of intratesticular androgen (14) or by means of treatment of rats with Adjudin (12) did not disrupt the TJ barrier, unlike all other epithelia, where a disruption of AJ can lead to TJ barrier damage (15,16). These findings indicate that a mechanism is in place at the BTB that permits AJ restructuring while maintaining TJ integrity.…”