NG2 glial cells are distributed extensively in the brain and receive glutamatergic and GABAergic inputs from neurons. They express voltage-gated Na+ channels, but fail to produce typical action potentials. The physiological role of Na+ channels in these cells is unclear. We found that GABA induces membrane depolarization and Ca2+ elevation in NG2 cells, a process requiring activation of GABAA receptors, Na+ channels, and Na+/Ca2+ exchangers (NCXs), but not Ca2+ channels. We have identified a persistent Na+ current in these cells that may underlie GABA-induced pathway of prolonged Na+ elevation, which in turn triggers Ca2+ influx via NCXs. This unique Ca2+ signaling pathway is further shown to be involved in GABA-induced chemotactic migration of NG2 cells. Thus, GABAergic signaling mediated by sequential activation of GABAA receptors, non-inactivating Na+ channels, and NCXs may play an important role in the development and function of NG2 glial cells in the brain.