Journal of Molecular Medicine

, Volume 78, Issue 1, pp 3–13

Molecular mechanisms of calcium-dependent excitotoxicity

  • Rita Sattler
  • Michael Tymianski

DOI: 10.1007/s001090000077

Cite this article as:
Sattler, R. & Tymianski, M. J Mol Med (2000) 78: 3. doi:10.1007/s001090000077


Excitotoxicity is thought to be a major mechanism contributing to neurodegeneration during central nervous system ischemia, trauma, and other neurological disorders. Briefly, synaptic overactivity leads to the excessive release of glutamate, the major excitatory neurotransmitter in the mammalian central nervous system. Glutamate activates a number of postsynaptic cell membrane receptors, which upon activation open their associated ion channel pore to produce ion influx or efflux. This leads to a disturbance of the intracellular ionic environment, the best characterized feature of which is the influx of sodium, chloride, and Ca2+. An excess of Ca2+ ions then activates intracellular Ca2+-dependent signaling cascades that eventually lead to neuronal cell death. Despite intensive research in the field of Ca2+-dependent neurotoxicity the precise molecular mechanisms leading to cell death remain poorly understood. In particular, the question of the precise relationship between Ca2+ loading and neurotoxicity has been controversial. Many glutamate receptors are clustered and localized at the postsynaptic density. Recently, increasing knowledge of the molecular composition of the postsynaptic density has allowed us to extend our understanding of the molecular mechanisms of Ca2+-dependent excitotoxicity and to propose that distinct, membrane receptor-specific, neurotoxic signaling pathways transduce Ca2+-dependent excitotoxicity. These findings may have significant implications in the search for precisely targeted therapeutic drugs for a range of neurological disorders.

Neurotoxicity Postsynaptic density NMDA receptor Calcium Cell death 

Copyright information

© Springer-Verlag 2000

Authors and Affiliations

  • Rita Sattler
    • 1
  • Michael Tymianski
    • 1
  1. 1.Toronto Western Hospital Research Institute, Division of Cellular and Molecular Neuroscience, Neuroprotection Laboratory, 399 Bathurst Street, Toronto, Ontario M5T 2S8, CanadaCanada
  2. 2.Present address: Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Department of Neuroscience, 725 North Wolfe Street, Baltimore, MD 21205, USA, e-mail:, Tel.: +1-410-9554052, Fax: +1-410-9554857USA

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