Cell membrane disruption stimulates NO/PKG signaling and potentiates cell membrane repair in neighboring cells

PLoS One. 2012;7(8):e42885. doi: 10.1371/journal.pone.0042885. Epub 2012 Aug 7.


Resealing of a disrupted plasma membrane at the micron-diameter range requires Ca(2+)-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclic GMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic GMP-Dependent Protein Kinases / metabolism*
  • Dogs
  • Madin Darby Canine Kidney Cells
  • Nitric Oxide / metabolism*
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • Signal Transduction* / drug effects
  • Wound Healing* / drug effects


  • Cyclic AMP Response Element-Binding Protein
  • Protein Kinase Inhibitors
  • Nitric Oxide
  • Cyclic GMP-Dependent Protein Kinases

Grant support

This study was supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.