Cyclin D1 induction preceding neuronal death via the excitotoxic NMDA pathway involves selective stimulation of extrasynaptic NMDA receptors and JNK pathway

Neuro-degenerative Diseases
L EfthimiadiS Krantic

Abstract

The N-methyl-D-aspartate subtype of ionotropic glutamate receptors (NMDARs) signals both prosurvival and death-inducing (excitotoxic) neuronal responses via synaptically (synaptic NMDAR) and extrasynaptically (extrasynaptic NMDAR) located receptor pools, respectively. Both receptor pools share similar, though not identical, postreceptor signaling molecules. The activation of the extrasynaptic NMDAR pathway is predominant. Therefore, in order to inhibit the extrasynaptic death pathway while sparing synaptic responses, it is critical to identify selective postreceptor effectors of extrasynaptic NMDARs. The present study addressed these issues by using primary cultures of rat hippocampal neurons and a pharmacological protocol of selective NMDAR stimulation for Western blot and immunocytochemistry analyses. We found that the activation of extrasynaptic NMDARs, either alone or together with synaptic NMDARs, triggers cyclin-D1-associated re-entry into the cell cycle, which does not proceed beyond the S-phase. This aberrant cell cycle re-entry is particularly associated with neuronal death triggered specifically via extrasynaptic NMDAR-induced c-Jun N-terminal protein kinase (JNK). In addition, NMDA-elicited neuronal death was signifi...Continue Reading

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Citations

Oct 7, 2015·Frontiers in Cellular Neuroscience·Stéphanie SeguraEmmanuel Moyse
Apr 13, 2015·Pathophysiology : the Official Journal of the International Society for Pathophysiology·Ibukun Dorcas AkinrinadeOlalekan Michael Ogundele
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Mar 1, 2018·Physiological Reviews·Michael FrickerGuy C Brown

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