Cytoskeletal breakdown and apoptosis elicited by NO donors in cerebellar granule cells require NMDA receptor activation

J Neurochem. 1996 Dec;67(6):2484-93. doi: 10.1046/j.1471-4159.1996.67062484.x.


We have recently demonstrated that nitric oxide (NO) donors can trigger either apoptosis or necrosis of neurons as a function of the intensity of the exposure. Here, we show that the apoptosis induced by the NO donors S-nitrosocysteine (SNOC) or S-nitroso-N-acetyl-penicillamine (SNAP) in cultured cerebellar granule cells (CGCs) depends on NMDA receptor (NMDA-R) activation leading to intracellular Ca2+ overload. Early dissolution of actin filaments followed by breakdown of microtubules and nuclear lamins preceded the appearance of typical apoptotic features. NO donors induced tyrosine nitration in neurons, in a small population of contaminating astrocytes, and in cultures of cerebellar astroglial cells. However, astrocytes neither displayed cytoskeletal alterations nor underwent apoptosis. Competitive and uncompetitive NMDA receptor antagonists, such as D-aminophosphonovaleric acid and MK-801, did not influence tyrosine nitration but prevented the accumulation of intracellular Ca2+, cytoskeletal breakdown, and apoptosis induced by either SNOC or SNAP in CGCs. Taken together, these data strongly suggest that Ca2+ influx through NMDA-R-gated ion channels is a critical event in CGC apoptosis induced by NO donors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Calcium / metabolism
  • Cells, Cultured / chemistry
  • Cells, Cultured / cytology
  • Cells, Cultured / metabolism
  • Cerebellum / cytology*
  • Cysteine / analogs & derivatives
  • Cysteine / pharmacology
  • Cytoskeleton / metabolism*
  • DNA Fragmentation / drug effects
  • Dizocilpine Maleate / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Nitric Oxide / physiology*
  • Penicillamine / analogs & derivatives
  • Penicillamine / pharmacology
  • Potassium / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • S-Nitroso-N-Acetylpenicillamine
  • S-Nitrosothiols*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Tyrosine / metabolism


  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • S-Nitrosothiols
  • Nitric Oxide
  • Tyrosine
  • Dizocilpine Maleate
  • S-Nitroso-N-Acetylpenicillamine
  • S-nitrosocysteine
  • Penicillamine
  • Cysteine
  • Potassium
  • Calcium