Evidence for Feedback Regulation of Glutamate Decarboxylase by Gamma-aminobutyric Acid

Although feedback control mechanisms for regulating the synthesis of various neurotransmitters have been demonstrated no such mechanism has been described for gamma-aminobutyric acid (GABA) in mammalian brain. Physiological concentrations of GABA inactivated glutamate decarboxylase, the enzyme responsible for GABA synthesis, by converting it to apoenzyme. This inactivation was opposed by the cofactor, pyridoxal 5'-phosphate (pyridoxal-P), and was promoted by ATP. GABA also competitively inhibited the enzyme, and the Ki for inhibition was essentially the same as the concentration of GABA giving the half-maximal rate of inactivation (16 mM). These results provide a mechanism for direct feedback control of presynaptic GABA synthesis and provide further support for the regulation of glutamate decarboxylase in vivo by a cycle of inactivation and reactivation.