In their experiments, the researchers discovered the molecular mechanism linking two key components of neuronal damage due to oxygen starvation, or ischemia. One component is a type of receptor called an NMDA receptor (NMDAR). This receptor is triggered by glutamate, which is known to be released during ischemia.
The other component of neuronal damage that they studied is an "acid-sensing ion channel," (ASIC)--basically, a pore-like protein in the membranes of neurons. In response to the acid unleashed by ischemia, ASICs open to admit calcium into the cell, and calcium overload is central to neuronal death.
In their experiments, Gao and colleagues induced ischemia in rat brains, or deprived cultured neurons of oxygen, and analyzed the molecular effects. Their analyses revealed that such deprivation triggered NMDARs, which in turn activated an important cell switch called CaMKII. This enzyme, they found, acts on a particular ASIC, called ASIC1a, to greatly enhance its sensitivity to the acid induced by ischemia. This increased sensitivity causes the ASIC channel to open and flood the neuron with lethal doses of calcium.
Importantly, the researchers found in cultures of neurons that drugs that inhibited NMDAR or CaMKII prevented the ischemia-induced enhancement of ASIC sensitivity, as well as neuronal death.
"In summary, our report provides a functional linkage between NMDAR-mediated exitotoxicity and ASIC-mediated acidotoxicity induced by ischemia, which is known to cause excessive glutamate release and acidosis. Both NMDARs and [calcium permeable] ASICs have now been implicated in ischemic neuronal damage.
"Our finding...sheds new light on the development of therapeutic agents against excitotoxic and acidotoxic neuronal damage," concluded the researchers. Also, they added, since such NMDARs and ASIC1a are involved in seizures and pain sensation, "a similar coupling between these two channels is likely to occur in these diseases as well."
The researchers include Jun Gao, Bo Duan, De-Guang Wang and Tian-Le Xu of the Chinese Academy of Sciences in Shanghai, China and the University of Science and Technology of China in Hefei, China; Xiao-Hong Deng and Lin Xu of the Chinese Academy of Sciences in Shanghai, China; Guang-Yi Zhang of Xuzhou Medical College in Xuzhou, China. This research was supported by the National Natural Science Foundation of China (Nos. Grants 30125015, 30321002), the National Basic Research Program of China (No. 2006CB500803), and the Knowledge Innovation Projects from the Chinese Academy of Sciences (KSCX 2-SW-217). J.G. is supported by the China Postdoctoral Science Foundation and the K.C. Wong Education Foundation.
Gao et al.: "Coupling between NMDA Receptor and Acid-Sensing Ion Channel Contributes to Ischemic Neuronal Death." Publishing in Neuron, Vol. 48, 635-646, November 23, 2005, DOI 10.1016/j.neuron.2005.10.011, www.neuron.org