Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text (PDF, 426K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wells, W. A. Search for Related Content PubMed Articles by Wells, W. A. Social Bookmarking                            What's this?

No exit for Ca²⁺

Glutamate-induced death (top) is rescued by inhibiting calpain. NICOTERA/ELSEVIER

Overexcited neurons go to their death because of a Ca²⁺ overdose, say Daniele Bano, Pierlugi Nicotera (University of Leicester, UK), and colleagues. The overdose is induced by a calpain protease, which chops up the exchanger that normally ferries Ca²⁺ out of the cell.

Neurons that are cut off from a blood supply and thus from oxygen fail to clear the neurotransmitter glutamate from their synapses. The result is overstimulation, including an excessive dose of intracellular calcium. Nicotera and colleagues show that this initial increase can subsequently be translated into a larger and potentially deadly overdose of Ca²⁺. The overdose occurs downstream of a calpain cleavage of the Na⁺/Ca²⁺ exchanger NCX3. The Ca²⁺ overload is blocked and necrotic cell death is reduced after inhibition of calpain or expression of the alternative NCX2 exchanger. Reduction of NCX3 function by siRNA results, however, in the opposite effect: treated neurons are sensitized to Ca²⁺-induced necrotic death.

NCX3 is a low affinity but high capacity exchanger, and thus is well suited to ferrying large amounts of Ca²⁺ out of the cell. It is not clear whether calpain's action to stop this restorative function is a form of deliberate suicide or of pathology. The calpain may be acting to eliminate defective cells and thus save the organism from potential damage, or it may be overdoing a normal calpain function, such as regulation of membrane protein turnover, resulting in an accidental pathology.

Reference:

Bano, D., et al. 2005. Cell. 120:275–285.[CrossRef][Medline]

William A. Wells

wellsw{at}rockefeller.edu

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This Article Full Text (PDF, 426K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wells, W. A. Search for Related Content PubMed Articles by Wells, W. A. Social Bookmarking                            What's this?