Kill or Cosset: Does location turn a protein bad? (Stroke)
Authors: Leslie Mitch 
Published: August 2003

Location is everything in real estate, and it might dictate whether a protein coddles or murders brain cells. Depending on where a particular receptor protein sits on the cell membrane, it can either kill or sustain the cell, according to a new study. The findings might allow scientists to develop ways of fending off brain damage during stroke or seizures.
The protein in question is the NMDA receptor, an antenna on the surface of brain cells. Stimulation of this antenna by chemical signals helps solidify memory and learning. However, NMDA has a puzzling split personality. Sometimes, stimulating the receptor kills the cell, but other times blocking it is lethal. According to Hilmar Bading, a molecular neuroscientist at the University of Heidelberg in Germany who led the study, the standard view held that the outcome depended on the concentration of glutamate, a neurotransmitter that activates NMDA. Large amounts of glutamate would slay the cell through overstimulation, the argument went, whereas smaller amounts would promote survival.
But Bading and colleagues suspected that the position of the receptors might be the crucial variable. Nerve cells communicate by sending neurotransmitters across a small gap between them, known as a synapse. Cells carry NMDA receptors not only on the small section of membrane that makes up the synapse but on other parts of the membrane as well. An earlier study by Bading and co-workers suggested that receptors on different areas of the membrane had opposite effects on a protein that turns on a "nurturing signal."
To test the importance of receptor position, Hardingham and colleagues monitored what happened to a network of cultured neurons when receptors in particular locations received stimulation. They applied chemicals that either prod the synaptic receptors alone or selectively block them while goading the other receptors. Activating the receptors within the synapse stimulated production of a protein that helps keep cells alive. The synaptically stimulated cells also resisted a chemical that triggers suicide better than did cells whose receptors outside the synapse were juiced. Blocking synaptic receptors and then activating the nonsynaptic receptors thwarted production of the life-promoting protein. The cells perished as their mitochondria lost the ability to generate energy.
The results are the first to suggest that receptor function depends on location, says Bading. Although the two kinds of receptors differ slightly in structure, scientists had thought they worked identically. The findings could lead to treatments that prevent damage during strokes, head injuries, and seizures, he says. All three conditions result in excess glutamate in the brain, which might injure and kill cells by triggering the external NMDA receptors. The study cautions drug developers that "you'd better stay away from those synaptic receptors," says Stuart Lipton, a neurologist and neuroscientist at the Burnham Institute in La Jolla, California. Bading says that structural differences between the two types of receptors should make it possible to design selective drugs: "This is not science fiction. This is within reach."
--Mitch Leslie

G. E. Hardingham, Y. Fukunaga, H. Bading, Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways.
Nat. Neurosci.
, 15 April 2002 [e-pub ahead of print].
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