In order to clarify the functional role of gamma-aminobutyric acid (GABA) in developing brain, we investigated the effect of GABA on the survival of embryonic rat striatal neurons in dissociated cell culture. Chronic exposure of striatal cultures to GABA resulted in a significant increase in the number of surviving neurons. The effect of GABA was concentration-dependent (1-1000 microM) and was blocked by a GABAA receptor antagonist, bicuculline (100 microM), or a GABAA chloride channel blocker, picrotoxin (100 microM), but not by a GABAB receptor antagonist, 2-hydroxysaclofen (100 microM). In addition, the GABAA receptor agonist muscimol mimicked the effect of GABA, promoting cell survival in a concentration-dependent manner (0.01-100 microM), while the GABAB receptor agonist baclofen (up to 100 microM) had no significant effect. The GABA-induced enhancement of neuronal survival was suppressed by the L-type voltage-dependent Ca2+ channel blockers nifedipine (1-3 microM) and nicardipine (1-5 microM). Protein kinase inhibitors, H-7 (10-30 microM) or genistein (3 microM), also suppressed GABA-induced enhancement of neuronal survival. These results suggest that stimulation of GABAA receptors enhances survival of embryonic striatal neurons, and that the effect is mediated by Ca2+ influx through L-type voltage-dependent Ca2+ channels, initiating intracellular signaling cascades that involve activation of H-7- and genistein-sensitive protein kinases.