The role of the Na+/Ca2+ exchanger (NCX) in neurons following ischaemia

The Na+/Ca2+ exchanger (NCX) is a bi-directional membrane ion transporter. Under normal conditions, the exchanger transports one calcium ion out of the cell and three sodium ions into the cell. This is known as the calcium exit, or “forward” mode. Under certain conditions, however, the exchanger can reverse and transport calcium ions into the cell (calcium entry mode). Because dysregulation of sodium and calcium homeostasis is an integral feature of ischaemic brain injury, the role of the NCX in neurons following ischaemia has been investigated using a number of in vitro and in vivo models. Studies using in vitro ischaemia-related models (hypoxia, glutamate) have produced conflicting results, with some showing that NCX activity is neuroprotective while others indicate that it is neurodamaging. The majority of in vivo studies using the focal cerebral ischaemia model indicate that blocking NCX activity is neurodamaging while increasing NCX activity is neuroprotective. We have reviewed the major in vitro and in vivo neuronal ischaemia-related NCX studies in an attempt to clarify the reason for the conflicting findings. The use of different ischaemia models and doubts as to the specificity of pharmacological NCX inhibitors and stimulators has contributed to the confusion over the role of the NCX in ischaemic brain injury. The development of NCX transgenic animals may help our understanding of the role of this ion exchanger in neurons following ischaemia and aid the development of an effective stroke treatment.