Glutamate decarboxylase

Glutamate decarboxylase or glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the decarboxylation of glutamate to GABA and CO 2. GAD uses PLP as a cofactor. The reaction proceeds as follows:


 * HOOC-CH 2 -CH 2 -CH(NH 2 )-COOH → CO 2 + HOOC-CH 2 -CH 2 -CH 2 NH 2

In mammals, GAD exists in two isoforms encoded by two different genes - Gad1 and Gad2. These isoforms are GAD67 and GAD65 with molecular weights of 67 and 65 kDa, respectively. GAD1 and GAD2 are expressed in the brain where GABA is used as a neurotransmitter, GAD2 is also expressed in the pancreas.

At least two more forms, GAD25 and GAD44 (embryonic; EGAD) are described in the developing brain. They are coded by the alternative transcripts of GAD1, I-80 and I-86: GAD25 is coded by both, GAD44 - only by I-80.

Diabetes
Both GAD67 and GAD65 are targets of autoantibodies in people who later develop type 1 diabetes mellitus or latent autoimmune diabetes. Injections with GAD65 has been shown to preserve some insulin production for 30 months in humans with type 1 diabetes.

Schizophrenia and bipolar disorder
Substantial dysregulation of GAD mRNA expression, coupled with downregulation of reelin, is observed in schizophrenia and bipolar disorder. The most pronounced downregulation of GAD67 was found in hippocampal stratum oriens layer in both disorders and in other layers and structures of hippocampus with varying degrees.

Parkinson disease
The bilateral delivery of glutamic acid decarboxylase (GAD) by an adeno-associated viral vector into the subthalamic nucleus of patients between 30 and 75 years of age with advanced, progressive, levodopa-responsive Parkinson disease resulted in significant improvement over baseline during the course of a six-month study.

Cerebellar disorders
Intracerebellar administration of GAD autoantibodies to animals increase the excitability of motoneurons and impairs the production of nitric oxide (NO), a molecule involved in learning. Epitope recognition contributes to cerebellar involvement.

Alteration by drugs
Pregabalin, an antiepileptic drug, increases neuronal GABA levels by producing a dose-dependent increase in glutamic acid decarboxylase activity. Extracts from Centella asiatica (gotu kola) and Valeriana officinalis (valerian) stimulated GAD activity.