Exchange to migrate

Activation of GABA_ARs (γ-aminobutyric acid type A receptors) leads to the elevation of intracellular Ca²⁺ concentration ([Ca²⁺]_i in immature neurons, through a well-established signalling pathway that is important for neuronal migration. NG2 cells — a group of glial precursors — also express GABA_ARs; however, the function of these receptors in NG2 cells was unknown. Tong et al. have now shown that the activation of GABA_ARs in NG2 cells triggers a different Ca²⁺ signalling pathway that involves reversal of the activity of the Na⁺–Ca²⁺ exchanger 1 (NCX1) and is required for the migration of NG2 cells during development.

The authors showed that activation of GABA_ARs led to increased [Ca²⁺]_i in cultured NG2 cells as well as in hippocampal slice preparations from juvenile rats, but not if the expression of non-inactivating Na⁺ channels or NCX1 was downregulated by small interfering RNAs or if these proteins were inhibited pharmacologically. They concluded that stimulation of GABA_ARs in NG2 cells activates non-inactivating Na⁺ channels, resulting in increased [Na⁺]_i that triggers reversal of the activity of NCXs and ultimately leads to increased [Ca²⁺]_i by exchanging intracellular Na⁺ for extracellular Ca²⁺.

The authors next tested whether this signalling mechanism is important for the migration of NG2 cells. NG2 cells in culture and from brain explants migrated towards a source of GABA. Pharmacological inhibition of GABA_ARs, Na⁺ channels or NCX1, or downregulation of Na⁺ channels or NCX1 expression using small interfering RNAs, impaired migration, providing evidence that the Ca²⁺ signalling mechanism investigated is important for the migration of NG2 cells.

This study shows that the signalling mechanisms that underlie GABA-induced Ca²⁺ elevation in NG2 cells and immature neurons, which is required for their migration, are very different. In neurons Ca²⁺ elevation is driven by voltage-gated Ca²⁺ channels and activation of N-methyl-D-aspartate receptors, whereas NG2 cells use the Ca²⁺ signalling pathway described above. It will be interesting to determine whether this signalling mechanism is also used by other migrating cells.