Excessive activation of cyclic nucleotide-gated channels contributes to neuronal degeneration of photoreceptors

Eur J Neurosci. 2005 Sep;22(5):1013-22. doi: 10.1111/j.1460-9568.2005.04306.x.


In different animal models, photoreceptor degeneration was correlated to an abnormal increase in cGMP concentration. The cGMP-induced photoreceptor toxicity was demonstrated by applying the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine on retinal explants. To assess the role of cGMP-gated channels in this cGMP toxicity, the Ca(2+) channel blockers verapamil and L- and D-diltiazem, which block cGMP-gated channels with different efficacies, were applied to in vitro animal models of photoreceptor degeneration. These models included: (i) adult rat retinal explants incubated with zaprinast, a more specific inhibitor of the rod phosphodiesterase than 3-isobutyl-1-methylxanthine and (ii) rd mouse retinal explants. Photoreceptor apoptosis was assessed by terminal dUTP nick end labelling and caspase 3 activation. Effects of the blockers on the synaptic rod Ca(2+) channels were measured by patch-clamp recording. In the zaprinast-induced photoreceptor degeneration model, both diltiazem isomers rescued photoreceptors whereas verapamil had no influence. Their neuroprotective efficacy was correlated to their inhibition of cGMP-gated channels (l-diltiazem>d-diltiazem>verapamil=0). In contrast, all three Ca(2+) channel blockers suppressed rod Ca(2+) channel currents similarly. This suppression of the currents by the diltiazem isomers was very weak (16.5%) at the neuroprotective concentration (10 microm). In rd retinal explants, both diltiazem isomers also slowed down rod degeneration in contrast to verapamil. L-diltiazem exhibited this effect at concentrations ranging from 1 to 20 microm. This study further supports the photoreceptor neuroprotection by diltiazem particularly in the rd mouse retina, whereas the absence of neuroprotection by verapamil further suggests the role of cGMP-gated channel activation in the induction of photoreceptor degeneration.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-3-isobutylxanthine / pharmacology
  • Animals
  • Animals, Newborn
  • Blotting, Western / methods
  • Cadmium Chloride / pharmacology
  • Calcium Channel Blockers / pharmacology
  • Cell Death / drug effects
  • Cells, Cultured
  • Cyclic Nucleotide-Gated Cation Channels
  • Diltiazem / pharmacology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • In Situ Nick-End Labeling / methods
  • In Vitro Techniques
  • Ion Channels / physiology*
  • Mice
  • Mice, Mutant Strains
  • Nerve Degeneration / pathology*
  • Nerve Degeneration / physiopathology*
  • Nerve Degeneration / prevention & control
  • Neuroglia / drug effects
  • Neuroglia / physiology
  • Phosphodiesterase Inhibitors / pharmacology
  • Photoreceptor Cells / drug effects
  • Photoreceptor Cells / pathology*
  • Purinones / pharmacology
  • Rats
  • Rats, Wistar
  • Swine
  • Verapamil / pharmacology


  • Calcium Channel Blockers
  • Cyclic Nucleotide-Gated Cation Channels
  • Ion Channels
  • Phosphodiesterase Inhibitors
  • Purinones
  • Verapamil
  • Diltiazem
  • zaprinast
  • Cadmium Chloride
  • 1-Methyl-3-isobutylxanthine