Researchers Find New Pathway To Brain Cell Suicide

In a study described in today’s Science, researchers at Washington University School of Medicine in St. Louis exposed brain cells and tissue to conditions that mimic those after stroke. They observed a flow of potassium ions out of the neurons, and this flow ebbed when they inactivated the NMDA receptor. Moreover, neurons that lost potassium committed suicide during the following days.

"This work provides evidence that potassium efflux through glutamate receptor channels may be one of the mechanisms that mediate programmed cell death of neurons," says lead author Shan Ping Yu, M.D., Ph.D., research associate professor of neurology. "And it is the first study to identify a consequence of potassium efflux through NMDA receptors."

Whereas necrotic cells swell up and burst, suicidal cells shrink into oblivion. A shrinking cell must be losing ions and water, Yu deduced, focusing on potassium because of its high concentration in cells. Although potassium was known to flow through voltage-gated potassium channels and the channel controlled by the NMDA receptor, the contribution of potassium movement through NMDA receptor channels to disease or normal physiology had not previously been studied.

Dennis W. Choi, M.D., Ph.D., the Andrew B. and Gretchen P. Jones Professor and head of neurology, directed the research team, and his long-time interests in the NMDA receptor and cell death initiated the current study. "These findings suggest that the participation of NMDA receptors in the pathogenesis of brain injury may be more multidimensional than previously suspected, and thus they increase the therapeutic rationale for developing drugs capable of blocking NMDA receptors," Choi says.

In the study, Yu made the first direct measurements of NMDA-evoked potassium currents from cortical neurons. The research team then looked at neurons cultured with glia, the brain’s housekeeping cells. When extracellular levels of sodium and calcium mimicked those in the healthy brain, NMDA (a glutamate-like chemical) killed the neurons by necrosis. But when sodium and calcium levels were low, as after brain injury, adding NMDA triggered apoptosis during the next one to two days. A chemical that blocks the action of NMDA inhibited both the cellular depletion of potassium and apoptosis, as did raising the concentration of potassium in the medium. According to Yu and other researchers, cellular potassium reduction may be a key step in activating apoptotic genes such as caspases. "This study provides evidence that the NMDA receptor may promote apoptosis by allowing potassium to escape from neurons," says Yu.

Next, the research team demonstrated that endogenous glutamate release also could cause neurons to lose potassium and undergo apoptosis if extracellular sodium and calcium levels were low. It appears, therefore, that glutamate released from brain cells can rob neighboring cells of potassium, facilitating their demise by programmed cell death.

"This work has opened a door for us to understand how and why glutamate triggers cell suicide after an ischemic insult," Yu says. "It eventually may provide a new opportunity to prevent or attenuate brain damage after harmful events such as stroke."

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Grants from the National Institutes of Health supported this research.

Yu SP, Yeh C-H, Strasser U, Tian M, Choi DW. NMDA receptor-mediated K+ efflux and neuronal apoptosis. Science vol. 284, April 9, 1999.