Glutamate decarboxylase

Glutamic acid decarboxylase 1
GAD67 derived from PDB: 2okj​
Identifiers
Symbol	GAD1
Alt. symbols	glutamate decarboxylase 1 (brain, 67kD); GAD67
Entrez	2571
HUGO	4092
OMIM	605363
RefSeq	NM_000817
UniProt	Q99259
Other data
EC number	4.1.1.15
Locus	Chr. 2 q31

Glutamate decarboxylase or glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the decarboxylation of glutamate to GABA and CO₂. GAD uses PLP as a cofactor. The reaction proceeds as follows:

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.

GAD₆₅ and GAD₆₇ synthesize GABA at different locations in the cell, at different developmental times, and for functionally different purposes. GAD₆₇ is spread evenly throughout the cell while GAD₆₅ is localized to nerve terminals. This difference is thought to reflect a functional difference; GAD₆₇ synthesizes GABA for neuron activity unrelated to neurotransmission, such as synaptogenesis and protection from neural injury. This function requires widespread, ubiquitous presence of GABA. GAD₆₅, however, synthesizes GABA for neurotransmission, and therefore is only necessary at nerve terminals and synapses. In order to aid in neurotransmission, GAD₆₅ forms a complex with Heat Shock Cognate 70 (HSC₇₀), cysteine string protein (CSP) and Vesicular GABA transporter VGAT, which, as a complex, helps package GABA into vesicles for release during neurotransmission. GAD₆₇ is transcribed during early development, while GAD₆₅ is not transcribed until later in life. This developmental difference in GAD₆₇ and GAD₆₅ reflects the functional properties of each isoform; GAD₆₇ is needed throughout development for normal cellular functioning, while GAD₆₅ is not needed until slightly later in development when synaptic inhibition is more prevalent.