Research Article: Cell Membrane Disruption Stimulates NO/PKG Signaling and Potentiates Cell Membrane Repair in Neighboring Cells

Date Published: August 7, 2012

Publisher: Public Library of Science

Author(s): Tatsuru Togo, Paul McNeil. http://doi.org/10.1371/journal.pone.0042885

Abstract

Resealing of a disrupted plasma membrane at the micron-diameter range requires Ca2+-regulated exocytosis. Repeated membrane disruptions reseal more quickly than the initial wound, and this potentiation of membrane resealing persists for at least 24 hours after the initial wound. Long-term potentiation of membrane resealing requires CREB-dependent gene expression, which is activated by the PKC- and p38 MAPK-dependent pathway in a wounded cell. The present study demonstrates that membrane resealing is potentiated in both wounded and neighboring cells in MDCK cells. Wounding of cells expressing CREB133, a mutant variant of CREB, does not show the potentiated response of cell membrane resealing in either wounded or neighboring cells. Furthermore, wounding of cells induces CREB phosphorylation, not only in wounded cells, but also in neighboring cells. Inhibition of the nitric oxide/PKG signaling pathway suppresses CREB phosphorylation in neighboring cells, but not in wounded cells. The potentiation of membrane resealing in neighboring cells is suppressed if the nitric oxide/PKG pathway is inhibited during the initial wound. Together, these results suggest that the nitric oxide/PKG pathway stimulates CREB phosphorylation in neighboring cells so that subsequent cell membrane disruptions of the neighboring cells reseal more quickly.

Partial Text

Mechanical stress induces disruptions of the plasma membranes of cells in various animal tissues under physiological conditions, and cells survive these disruptions by resealing the cell membrane [1]. Mechanisms for membrane resealing may differ depending on the size of the lesion. For large cell membrane lesions, homotypic vesicle-vesicle fusion may occur to create a membrane “patch” [2], [3]. However, small micron-diameter disruptions evoke the Ca2+-dependent exocytosis of vesicles near the wound site, which is essential for successful membrane resealing [4], [5], [6], [7], [8], [9], [10]. This small disruption reaction has a lower Ca2+ threshold than that for “patch” formation [1]. It has been proposed that wound-induced exocytosis promotes resealing by lowering the plasma membrane tension [11]. In addition to mechanical disruption of the plasma membrane, cells also respond to the other form of lesions. For example, stable lesions induced by bacterial pore-forming toxin are removed from the cell membrane by endocytosis [12].

Plasma membrane disruption at the micron-diameter range evokes a rapid exocytosis, which is essential for successful membrane resealing [1]. It has been previously demonstrated that repeated membrane disruption reveals long-term potentiation of Ca2+-regulated exocytosis in 3T3 fibroblasts, which is closely correlated with faster membrane resealing rates at repeated wounds [13]. This potentiation of exocytosis and membrane resealing depends on gene expression that is mediated by the transcription factor CREB via a PKC- and p38 MAPK-dependent pathway in a wounded cell. In addition to wounded cells, the present study demonstrates that wounding of MDCK cells potentiates membrane resealing in neighboring cells in a CREB-dependent manner. Since many organs in animals normally generates and/or receive considerable levels of mechanical stress repetitively, and since these stresses often result in the cell membrane disruptions [1], the multicellular adaptive response leading to faster cell membrane resealing at subsequent woundings may minimize the toxic effects of excessive Ca2+ influx into cells [26] and the loss of crucial cellular constituents from cells, and may protect tissues from mechanical stresses efficiently.

Source:

http://doi.org/10.1371/journal.pone.0042885