Biochemical consequences of reactions catalyzed by GAD and GABA-T

Abstract

GABA-T abstracts the pro-4-S proton from GABA. The enzyme abstracts the analogous protons from (+)-γ-acetylenic GABA and (+)-γ-vinyl GABA in each case precipitating its own inactivation. (+)-γ-Acetylenic GABA also irreversibly inhibits GAD indicating a transamination capability of the decarboxylase on this synthetic GABA analogue. γ-Vinyl GABA has no effect on this enzyme in vitro. Administration of either γ-acetylenic or γ-vinyl GABA to rats or mice results in a dose-dependent increase in brain GABA levels. At any given level of GABA-T inhibition the concentrations of GABA are higher after γ-vinyl GABA due to its smaller effect on GAD. Nevertheless, after a dose of γ-vinyl GABA sufficient to raise brain GABA levels to over 300% of control levels for 48 hours, there is a slow decrease in brain GAD activity to 75% and 65% of control levels at 24 and 48 hours respectively. This diminution of GAD activity after administration of γ-vinyl GABA is consistent with a feedback effect of sustained elevated GABA levels on the synthesis of GAD.