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(Stroke. 2007;38:674.)
© 2007 American Heart Association, Inc.

Glutamate-Independent Calcium Toxicity: Introduction

Ca²⁺ Signals and Neuronal Death in Brain Ischemia

Daniele Bano, PhD Pierluigi Nicotera, MD, PhD

From the Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Leicester, UK.

Correspondence to Pierluigi Nicotera, MD, PhD, Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, PO Box 138, Lancaster Rd LE1 9HN, Leicester, UK. E-mail pn10{at}le.ac.uk

Abstract

Although Ca²⁺ signals are necessary for cell communication and survival, abnormal cellular Ca²⁺ load can trigger different cell death programs. Ca²⁺ mediates cell death by activating proteases (ie, calpains), by reinforcing signals leading to caspase activation or by triggering other catabolic processes mediated by lipases and nucleases. Failure in the clearance of excitatory amino acid is a critical determinant of neuronal loss in the ischemic brain. Glutamate activates glutamate-ionotropic receptors at synaptic and extra-synaptic sites, causing prolonged neuronal depolarization and triggering deregulation of cellular ion homeostasis, mainly intracellular calcium and sodium. The mechanisms leading to the sustained calcium deregulation in excitotoxic conditions are only in part elucidated. Recently, we have shown that calpains mediate the inhibition of calcium efflux in primary dissociated neurons challenged with excitotoxic glutamate concentrations. Calpains cleave the sodium-calcium exchanger (NCX) and inhibit its capability to remove calcium accumulated as a consequence of the excitotoxic stimulus. Our findings highlight the link between calcium-dependent proteases, calcium overload and neuronal degeneration after an excitotoxic insult.

Key Words: calcium transporter • cell cultures • neurochemistry • neuroprotection

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