CYTOSKELETAL BREAKDOWN AND APOPTOSIS ELICITED BY NO DONORS IN CEREBELLAR GRANULE CELLS REQUIRE NMDA RECEPTOR ACTIVATION

We have recently demonstrated that nitric oxide (NO) donors can trigge r either apoptosis or necrosis of neurons as a function of the intensi ty of the exposure. Here, we show that the apoptosis induced by the NO donors S-nitrosocysteine (SNOC) or S-nitroso-N-acetylpenicillamine (S NAP) in cultured cerebellar granule cells (CGCs) depends on NMDA recep tor (NMDA-R) activation leading to intracellular Ca2+ overload. Early dissolution of actin filaments followed by breakdown of microtubules a nd nuclear lamins preceded the appearance of typical apoptotic feature s, NO donors induced tyrosine nitration in neurons, in a small populat ion of contaminating astrocytes, and in cultures of cerebellar astrogl ial cells. However, astrocytes neither displayed cytoskeletal alterati ons nor underwent apoptosis. Competitive and uncompetitive NMDA recept or antagonists, such as D-aminophosphonovaleric acid and MK-801, did n ot influence tyrosine nitration but prevented the accumulation of intr acellular Ca2+, cytoskeletal breakdown, and apoptosis induced by eithe r SNOC or SNAP in CGCs, Taken together, these data strongly suggest th at Ca2+ influx through NMDA-R-gated ion channels is a critical event i n CGC apoptosis induced by NO donors.