The role of Na+/Ca2+ exchanger subtypes in neuronal ischemic injury

The Na(+)/Ca(2+) exchanger (NCX) plays an important role in the maintenance of Na(+) and Ca(2+) homeostasis in most cells including neurons under physiological and pathological conditions. It exists in three subtypes (NCX1-3) with different tissue distributions but all of them are present in the brain. NCX transports Na(+) and Ca(2+) in either Ca(2+)-efflux (forward) or Ca(2+)-influx (reverse) mode, depending on membrane potential and transmembrane ion gradients. During neuronal ischemia, Na(+) and Ca(2+) ionic disturbances favor NCX to work in reverse mode, giving rise to increased intracellular Ca(2+) levels, while it may regain its forward mode activity on reperfusion. The exact significance of NCX in neuronal ischemic and reperfusion states remains unclear. The differential role of NCX subtypes in ischemic neuronal injury has been extensively investigated using various pharmacological tools as well as genetic models. This review discusses the mode of action of NCX in ischemic and reperfusion states, the differential roles played by NCX subtypes in these states as well as the role of NCX in pre- and postconditioning. NCX subtypes carry variable roles in ischemic injury. Furthermore, the mode of action of each subtype varies in ischemia and reperfusion states. Thus, therapeutic targeting of NCX in stroke should be based on appropriate timing of the administration of NCX subtype-specific strategies.