Purpose of Glutamic Acid Decarboxylase (GAD)
Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme that catalyzes the conversion of glutamate to gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system. 1, 2
Primary Physiological Function
- GAD performs the one-step biosynthesis of GABA from L-glutamate, serving as the critical enzyme controlling inhibitory neurotransmission in the brain 1, 3
- The enzyme exists in two isoforms—GAD65 and GAD67—which have distinct intraneuronal distributions and functional roles 4
Isoform-Specific Roles
GAD67 Distribution and Function
- GAD67 is widely distributed throughout neurons and exists almost entirely as active holoenzyme saturated with its cofactor pyridoxal phosphate 4
- This form appears to maintain basal GABA levels throughout the neuron 4
GAD65 Distribution and Function
- GAD65 is concentrated primarily in axon terminals where GABA is released 4
- Only approximately half of GAD65 exists as active holoenzyme, with the remainder present as inactive apoenzyme 4
- The ratio of active to inactive GAD65 in synaptic terminals couples GABA production to neuronal activity, providing activity-dependent regulation of neurotransmitter synthesis 4
- GAD65 functions as a Ca²⁺-dependent peripheral membrane protein that associates with synaptic vesicles during nerve terminal depolarization through a reversible process 3
Clinical Significance
Autoimmune Targeting
- GAD serves as a major autoantigen in both type 1 diabetes and neurological autoimmune disorders 5, 6
- In type 1 diabetes, autoantibodies to GAD65 (along with other islet autoantibodies) mark immune-mediated destruction of pancreatic β-cells 5, 6
- High titers of GAD antibodies are associated with neurological syndromes including stiff-person syndrome, cerebellar ataxia, limbic encephalitis, and drug-resistant epilepsy 6, 2, 7
Pathophysiological Mechanisms
- GAD antibody-mediated inhibition of the enzyme leads to decreased GABA synthesis, resulting in reduced inhibitory neurotransmission 8, 2
- In stiff-person syndrome specifically, this GABA deficiency manifests as progressive spasmodic muscular rigidity and painful muscle spasms 8
- The antibodies may reduce GABA synthesis in nerve terminals or interfere with GABA exocytosis 2
Common Pitfalls
- Do not confuse GAD (glutamic acid decarboxylase) with gadolinium-based contrast agents (GBCAs), which are completely unrelated substances despite similar abbreviations 5
- The presence of GAD antibodies indicates autoimmune activity but does not necessarily mean the enzyme itself is dysfunctional—rather, the immune response targeting GAD causes pathology 6, 7