GABAdegrading

GABA degradation refers to the biochemical processes that break down gamma-aminobutyric acid (GABA) after its release as an inhibitory neurotransmitter. The degradation pathway helps terminate GABA signaling and can feed carbon into energy metabolism via the GABA shunt.

The primary enzymatic steps are catalyzed by GABA transaminase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH). In the main reaction, GABA is transaminated with alpha-ketoglutarate to produce succinic semialdehyde and glutamate. Succinic semialdehyde is then oxidized to succinate, which enters the tricarboxylic acid cycle.

GABA degradation is complemented by reuptake of GABA into neurons and astrocytes via GABA transporters (GATs). Regulation of degradation and transport coordinates termination of GABAergic signaling and prevents excessive GABA accumulation.

Disruptions in degradation enzymes have clinical consequences. SSADH deficiency causes elevated GABA and gamma-hydroxybutyrate, with developmental delay, hypotonia, and seizures. Inhibitors of GABA-T, such as vigabatrin, increase GABA levels to treat refractory epilepsy, but may cause vision problems.

In the brain, GABA degradation occurs in discrete cellular compartments, with astrocytes contributing to metabolism. The rate of degradation varies by region and activity, and interacts with GABA synthesis and transport to shape inhibitory neurotransmission.