The endoplasmic reticulum of most cell types mainly consists of an extensive network of narrow sheets and tubules. It is well known that an excessive increase of the cytosolic Ca(2+) concentration induces a slow but extensive swelling of the endoplasmic reticulum into a vesicular morphology. We observed that a similar extensive transition to a vesicular morphology may also occur independently of a change of cytosolic Ca(2+) and that the change may occur at a time scale of seconds. Exposure of various types of cultured cells to saponin selectively permeabilized the plasma membrane and resulted in a rapid swelling of the endoplasmic reticulum even before a loss of permeability barrier was detectable with a low-molecular mass dye. The structural alteration was reversible provided the exposure to saponin was not too long. Mechanical damage of the plasma membrane resulted in a large-scale transition of the endoplasmic reticulum from a tubular to a vesicular morphology within seconds, also in Ca(2+)-depleted cells. The rapid onset of the phenomenon suggests that it could perform a physiological function. Various mechanisms are discussed whereby endoplasmic reticulum vesicularization could assist in protection against cytosolic Ca(2+) overload in cellular stress situations like plasma membrane injury. (C) 2011 Elsevier Inc. All rights reserved.