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NMDA receptor-dependent excitotoxicity: the role of intracellular Ca2+ release
1Department of Neurology, Reed Neurological Research Center, UCLA School of Medicine 90095-1769, USA.
Abstract:
Massive activation of glutamate receptors can result in excessive rises in cytoplasmic Ca2+ that are thought to underlie the fundamental processes ultimately leading to neuronal death. Preventing such cellular Ca2+ rises in the brain may reduce considerably the neuronal damage produced by stroke, head trauma, or epilepsy. Activation of NMDA receptors is instrumental in this type of neurotoxicity. Recent findings, discussed here by Istvan Mody and John MacDonald, indicate that a large proportion of the neurotoxic Ca2+ that enters nerve cells following NMDA receptor activation originates from an intracellular Ca2+ pool. The release of Ca2+ from this pool is sensitive to the skeletal muscle relaxant dantrolene, and this may constitute a novel and alternative therapeutic approach against NMDA receptor-mediated excitotoxicity.
Insights
Excessive calcium influx into neurons, triggered by glutamate receptor activation, causes neuronal death. Targeting intracellular calcium release with dantrolene may offer a new treatment for excitotoxicity from stroke, head trauma, and epilepsy.
Area of Science:
- Neuroscience
- Cellular Biology
- Pharmacology
Background:
- Glutamate receptor overactivation leads to excessive intracellular calcium (Ca2+), a key factor in neuronal death.
- This excitotoxicity is implicated in brain damage from stroke, head trauma, and epilepsy.
- NMDA receptors play a critical role in this neurotoxic process.
Purpose of the Study:
- To investigate the origin of neurotoxic Ca2+ influx following NMDA receptor activation.
- To explore the potential of targeting intracellular Ca2+ pools as a therapeutic strategy against NMDA receptor-mediated excitotoxicity.
Main Methods:
- Analysis of Ca2+ dynamics in neurons following NMDA receptor stimulation.
- Assessment of the effect of dantrolene on intracellular Ca2+ release.
Main Results:
- A significant portion of neurotoxic Ca2+ influx originates from an intracellular Ca2+ pool.
- The release of Ca2+ from this intracellular pool is sensitive to dantrolene.
Conclusions:
- Intracellular Ca2+ stores are a major source of excitotoxicity mediated by NMDA receptors.
- Dantrolene's ability to inhibit Ca2+ release from these stores presents a novel therapeutic avenue for NMDA receptor-mediated excitotoxicity.