No exit for Ca²⁺

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...