NG2 cells originate from various brain regions and migrate to their destinations during early development. These cells 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 Ca(2+) elevation in NG2 cells, a process requiring activation of GABA(A) receptors, Na(+) channels, and Na(+)/Ca(2+) exchangers (NCXs), but not Ca(2+) channels. We have identified a persistent Na(+) current in these cells that may underlie the GABA-induced pathway of prolonged Na(+) elevation, which in turn triggers Ca(2+) influx via NCXs. This unique Ca(2+) signaling pathway is further shown to be involved in the migration of NG2 cells. Thus, GABAergic signaling mediated by sequential activation of GABA(A) receptors, noninactivating Na(+) channels, and NCXs may play an important role in the development and function of NG2 glial cells in the brain.