Sustained elevation of intracellular cGMP causes oxidative stress triggering calpain-mediated apoptosis in photoreceptor degeneration

Curr Eye Res. 2007 Mar;32(3):259-69. doi: 10.1080/02713680601161238.


Sustained elevation in cGMP and a concomitant increase in intracellular Ca(2+) levels in the rd1 photoreceptors are followed by a rapid loss of photoreceptors. In a murine-derived photoreceptor cell line, 661W, treated with the phosphodiesterase inhibitor IBMX or the cyclic GMP-gated channel agonist 8-bromo-cGMP, it was previously found that the induced cell death was mediated by calpain and caspase-3. Because oxidative stress is a common product of ionic imbalance or elevated Ca(2+), we tested the role of oxidative stress in cGMP-induced photoreceptor cell death. In the rd1 mouse retina, oxidative stress was found to precede calpain and caspase-3 activation. In 661W cells, the increase in intracellular cGMP and Ca(2+) resulted in the generation of reactive oxygen species (ROS), the activation of oxidative stress enzymes, and the activation of calpain, followed by apoptosis mediated by the effector caspase-3. All these events, including calpain activation, were ameliorated by docosahexanoic acid (DHA). The cell-permeable inhibitor of calpain, SJA6017, while inhibiting cell death, had no effect on the generation of oxidative stress. These results establish a central role for oxidative stress in cGMP-induced cell death and suggest a ROS-mediated sequential activation of signal transduction events, which provide targets for future treatment strategies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-3-isobutylxanthine / pharmacology
  • Animals
  • Apoptosis*
  • Calcium / metabolism
  • Calpain / metabolism*
  • Caspase 3 / metabolism
  • Catalase / metabolism
  • Cell Line
  • Cell Survival
  • Cyclic GMP / metabolism*
  • Cytochromes c / metabolism
  • Docosahexaenoic Acids / pharmacology
  • Glutathione Peroxidase / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Oxidative Stress*
  • Phosphodiesterase Inhibitors / pharmacology
  • Photoreceptor Cells, Vertebrate / metabolism*
  • Photoreceptor Cells, Vertebrate / pathology
  • Reactive Oxygen Species / metabolism
  • Retinal Degeneration / metabolism*
  • Retinal Degeneration / pathology


  • Phosphodiesterase Inhibitors
  • Reactive Oxygen Species
  • Docosahexaenoic Acids
  • Cytochromes c
  • Catalase
  • Glutathione Peroxidase
  • Calpain
  • Caspase 3
  • Cyclic GMP
  • Calcium
  • 1-Methyl-3-isobutylxanthine