Acid-sensing ion channels
One major project in Dr. Xiong's laboratory is to study the molecular mechanisms underlying acidosis-mediated brain injury. During hypoxia/ischemia, for example, increased anaerobic glycolysis due to the lack of blood and oxygen supply leads to lactic acid accumulation, causing decreases in brain pH, a phenomenon termed acidosis. Extracellular pH typically falls to 6.5 during ischemia, and can fall below 6.0 during severe ischemia or under hyperglycemic conditions (e.g. in diabetic patients). For many years, acidosis has been known to play an important role in the pathology of neuronal injury. However, the cellular and molecular mechanisms underlying acidosis-mediated brain injury remained hypothetical, multifactorial and vague. Recent studies by Dr. Xiong's lab and his collaborators have demonstrated that activation of acid-sensing ion channels (ASICs), a novel family of proton-gated cation channels, and subsequent intracellular calcium overload, plays an important role in acidosis-mediated, glutamate-independent neuronal injury (Cell 118: 687-98, 2004). The blockade of these channels showed a promising protective time window of more than 5 hours (Brain 130:151-8, 2007). Thus, ASICs represent novel therapeutic targets for ischemic brain injury. Current studies in the lab focus on down-stream signaling pathways involved in the activation of ASICs, on targeting mechanisms of these channels to the cell surface membrane, on changes in the expression of ASICs, and on modulations of the channels by ischemia-related signaling molecules. The roles of ASICs in other neurological disorders are under active investigation.
Transient receptor potential (TRP) channels belong to a novel family of cation channels that are highly expressed in various tissues including the brain. Several members of the TRP family can be activated by oxidative stress and oxygen free radicals, both of which play important roles in neuronal injury associated with neurological disorders. Recent work by Dr. Xiong’s laboratory and his collaborators have indicated that calcium and/or zinc entry through TRPM7 channels, a member of the melastatin subfamily of the TRP channels, plays a key role in neuronal cell death associated with brain ischemia (Cell, 115: 863-77, 2003; JBC 285: 7430-9, 2010). The role of TRPM7 channels in other neurological diseases is also under investigation.
Current Grant Support
National Institute of Health (NIH)
American Heart Association (AHA)
Alzheimer’s Association (ALZ)
International Journal of Physiology Pathophysiology and Pharmacology, Editor-in-Chief
Neurological Research, Editorial Board Member
International Journal of Experimental and Clinical Medicine, Editorial Board Member