Previously we showed that the activity of the gamma-aminobutyric acid-synthesizing enzyme L-glutamate decarboxylase (GAD) in crude brain extract is inhibited by ATP and protein phosphatase inhibitors. We suggested that GAD activity is regulated by protein phosphorylation. In this paper we further present evidence to support our hypothesis that protein kinase A and calcineurin may be involved in regulation of GAD activity through phosphorylation and dephosphorylation fo GAD, respectively. In addition, the effect of neuronal stimulation on GAD activity in cultured neurons is also included. A model to link neuronal excitation and activation of GAD by Ca(2+)-dependent phosphatase is proposed.