Transmembrane fluxes are major determinants of several enzyme activities localized in the luminal compartment of the endoplasmic reticulum (ER). Although a large number of metabolites were shown to be transported across the ER membrane, only a few transporters have been identified so far. It can be assumed that the basal permeability of ER membrane vesicles (microsomes) to a variety of small molecules is due to the presence of a low-selectivity channel or pore rather than many strictly specific transporters. The translocon complex is a possible candidate for this role because it transitionally forms an open channel in the ER membrane and an increasing amount of evidence shows the permeation of small compounds through this channel. It seems plausible that the translocon pore is not only responsible for inward and outward peptide translocation but also contributes to basal Ca(2+) leakage from the ER and ensures the substrate supply for certain luminal ER enzymes.