Elsevier

Cell Calcium

Volume 47, Issue 2, February 2010, Pages 122-129
Cell Calcium

Review
Calcium, ischemia and excitotoxicity

https://doi.org/10.1016/j.ceca.2010.01.003Get rights and content

Abstract

The initial reports regarding a cytotoxic role of calcium ions were published over 30 years ago. In neurons, calcium ions can gain entry into the cell through several mechanisms. These include the over-activation of glutamate receptors (NMDA, AMPA, KA) or of a range of channels and transporters (TRPM2, TRPM7, NCX, ASICs, CaV1.2, and hemichannels). Potentially toxic cytoplasmic calcium concentrations can also occur due to release from internal stores, either through physical damage to mitochondria and the endoplasmic reticulum, or a malfunction of receptors and channels present in their membranes. Such increases of cytoplasmic calcium concentrations can trigger a range of downstream neurotoxic cascades, including the uncoupling mitochondrial electron transfer from ATP synthesis, and the activation and overstimulation of enzymes such as calpains and other proteases, protein kinases, nitric oxide synthase (NOS), calcineurin and endonucleases. Despite the toxic role of calcium, drugs designed to block its entry into neurons have all failed to have any beneficial effects in clinical trials. We suggest that blocking certain receptors and ion channels is unlikely to be a useful therapeutic strategy due to potential deleterious side effects. However, identifying those that are most responsible for cell death and their downstream signalling pathways may lead to improved strategies for treating ischemic and excitotoxic disorders.

Section snippets

Excitotoxicity and ischemia

An interruption of blood supply to the brain during ischemic stroke results in oxygen and glucose deprivation and thus, a reduction in energy available to support the brain's cells [1]. Neurons in particular become unable to maintain the ionic gradients necessary for cellular function and homeostasis. This results in excessive neuronal depolarization, release of excitatory neurotransmitters, and reduced neurotransmitter re-uptake from the extracellular space. This process ultimately leads to

Excitotoxic mechanisms

Despite the ubiquitous presence of Ca2+ ions in cells, different physiological Ca2+-dependent processes, including synaptic plasticity and gene expression, are separately regulated through distinct signalling pathways are linked to specific routes of Ca2+ influx [14], [15]. Several routes of calcium ion entry into the cells exist and many of them are dysregulated after excitotoxicity, anoxia, or brain ischemia (Fig. 1). By restricting Ca2+ entry into cells to distinct pathways using

Release of calcium from internal stores

Ca2+ ions may gain access to the neuronal cytoplasm via ion channels or Ca2+ transport systems, or through the release of Ca2+ ions from intracellular stores. Depletion of calcium ions from the endoplasmic reticulum (ER) has been suggested as an initial signal for ER dysfunction in ischemic neurons [66]. Many studies indicate that a strong release of calcium ions from ER is associated with damage to cells, including damage to neurons after ischemia [67]. Chen et al. reported that dysregulation

Results of a rapid intracellular Ca2+ concentration rise in neuronal cells after ischemia

When cytoplasmic calcium concentrations reach non-physiological levels, several mechanisms are activated to remove lower [Ca2+]i. However, such systems fail or are insufficient in excitotoxicity or ischemia. Unchecked influx of Ca2+ can trigger apoptotic as well as necrotic death [4], [6], [53] (Fig. 3). Excess of Ca2+ ions concentrations activate proteases, lipases, phosphatases and endonucleases. Their over-activation may result in the damage of cell structures and further oxidative stress. Ca

Summary

The initial studies attributing cytotoxic actions to Ca2+ ions were published over 30 years ago [7], [8], [9]. Despite significant research in the intervening years the exact mechanisms of Ca2+ cytotoxicity remain incompletely characterized. Ca2+ overload can trigger many downstream neurotoxic cascades, including the uncoupling mitochondrial electron transfer from ATP synthesis, and the activation and overstimulation of enzymes such as calpains and other proteases, protein kinases, nitric oxide

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