isoformsGAD65

IsoformsGAD65 refers to the 65-kilodalton isoform of the enzyme glutamate decarboxylase, which catalyzes the conversion of glutamate to gamma-aminobutyric acid (GABA). In humans, GAD65 is encoded by the GAD2 gene and is one of two major glutamate decarboxylase isoforms, the other being GAD67, encoded by GAD1. GAD65 is primarily expressed in GABAergic neurons and is also present in pancreatic islets, where it serves as an autoantigen in type 1 diabetes.

GAD65 is a cytosolic enzyme that can associate with membranes in nerve terminals, a property that links its activity to synaptic demand. It tends to be synthesized as an inducible pool that responds to neuronal activity, providing GABA for rapid neurotransmission during periods of heightened signaling. Its regulation involves mechanisms such as phosphorylation and post-translational modifications that influence its membrane association and activity. GAD65 operates as a homodimer and requires the cofactor pyridoxal phosphate (PLP) for catalysis.

Physiologically, GAD65 contributes to the activity-dependent supply of GABA in presynaptic terminals, complementing GAD67, which provides a more constitutive baseline level of GABA synthesis. The two isoforms have distinct expression patterns and regulatory properties, supporting different modes of GABA production in the brain. In peripheral tissues, including the pancreas, GAD65’s presence is notable mainly as a target of autoantibodies rather than as a major regulator of metabolism.

Clinically, GAD65 is a well-known autoantigen in type 1 diabetes, with autoantibodies against GAD65 used in disease characterization. Research into GAD65 also informs understanding of GABAergic signaling and its dysregulation in neurological conditions.

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