It is now evident that the zonula occludens plays an essential role in the selective passage of substances from one side of an epithelium to the other. The ability of epithelia to create a diffusion barrier is controlled by two distinct  pathways for transport of substances across the epithelia (Fig. 5.17a):  The transcellular pathway occurs across the plasma membrane of the epithelial cell. In most of these pathways, transport is active and requires specialized energy-dependent membrane transport proteins and channels. These proteins and channels move selected substances across the apical plasma membrane into the cytoplasm and then across the lateral membrane below the level of the occluding junction into the intercellular compartment.
 The paracellular pathway occurs across the zonula occludens between two epithelial cells. The amount of water, electrolytes, and other small molecules transported through this pathway is contingent on the tightness of the zonula occludens. The permeability of an occluding junction depends on the molecular composition of the zonula occludens strands and thus the number of active aqueous channels in the seal (see the following section). Under physiologic conditions, substances transported through this pathway may be regulated or coupled to transcellular transport.
Permeability of the zonula occludens depends not only on the complexity and number of strands but also on the presence of functional aqueous channels formed by various claudin molecules.
TABLE Major Proteins Localized Within the Zonula Occludens Junction 5.3 Zona Occludens Protein Associated Protein Partners Function Occludin Occludin, ZO-1, ZO-2, ZO-3, Is present in most occluding junctions; maintains barrier Vap33, actin between apical and lateral cell surface Claudin Claudin, ZO-1, JAM Forms backbone of zonula occludens strands; forms and regulates aqueous channels used for paracellular diffusion JAM JAM, ZO-1, claudin Present in endothelial cells; mediates interactions between endothelial cells and monocyte adhesions ZO-1 ZO-2, ZO-3, occludin, claudin, Important link in transduction of signals from all JAM, cingulin, actin, ZONAB, transmembrane proteins; interacts with actin flaments; ASIP, AF-6 has tumor-suppressor actin ZO-2 ZO-1, occluding, cingulin, 4.1R Required in the epidermal growth factor–receptor signaling mechanism ZO-3 ZO-1, occludin, actin Interacts with ZO-1, occludin, and actin flaments of cell cytoskeleton AF-6 RAS, ZO-1 Small protein involved in molecular transport system and signal transduction Cingulin ZO-1, ZO-2, ZO-3, cingulin, Acidic, heat-stable protein that cross-links myosin II actin flaments into sedimentable complexes Symplekin CPSF-100 Dual-location protein: localized in zonula occludens and in the interchromatin particles of the karyoplasm ASIP/Par3 PKC Controls relocation of asymmetrically distributed proteins Rab3b GTPase Rab13 -PDE Rab8 G/C kinase, Sec4 Sec4 Rab8 GTPase required for polarized delivery of cargo vesicles to plasma membrane Sec6 Sec8 Participates in fusion of Golgi vesicle with the plasma membrane Sec8 Sec6 Inhibits basolateral translocation of LDLP receptors after formation of zonula occludens Members of the RAS oncogene family of proteins; control the assembly of protein complexes for docking of transport vesicles