GABA synthesis

Pyridoxal phosphate (ll.lOSf) is an essential coenzyme in the synthesis of y-aminobutyric acid (GABA) (11.93), which occurs in nerve terminals in the brain. 

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Sonnewald, U., Westergaard, N., Schousboe, A. etal. Direct demonstration by [13C]NMR spectroscopy that glutamine from astrocytes is a precursor for GABA synthesis in neurons. Neurochem. Int. 22 19-29,1993. 

GABA synthesis inhibitors act on the enzymes involved in the decarboxylation and transamination of GABA. Glutamic acid decarboxylase (GAD), the first enzyme in GABA biosynthesis, is inhibited easily by carbonyl reagents such as hydrazines [e.g., hydrazinopropionic acid (4.164) or isonicotinic acid hydrazide (4.165)], which trap pyridoxal, the essential cofactor of the enzyme. A more specific inhibitor is allylglycine (4.166). All of these compounds cause seizures and convulsions because they decrease the concentration of GABA. 

Jin H, Wu H, Osterhaus G, Wei J, Davis K, Sha D, Floor E, Hsu CC, Kopke RD, Wu JY (2003) Demonstration of functional coupling between gamma -aminobutyric acid (GABA) synthesis and vesicular GABA transport into synaptic vesicles. Proc Natl Acad Sci USA 100 4293 1298. 

GABA synthesis, probably by inhibiting GABA transaminase activity, but the dose of drug necessary to achieve this effect is very high and not relevant to the clinical situation. One possibility is that valproate desensitizes GABA autoreceptors and thereby facilitates the release of the transmitter. 

Sonnewald, U., Olstad, E., Qu, H., Babot, Z., Cristofol, R., Sunol, C., Schousboe, A., and Waagepetersen, H. 2004. First direct demonsfi ation of extensive GABA synthesis in mouse cerebellar neuronal culturQs. J Neurochem 91, 796—803. 

Battaglioli G, Liu H, Martin DL (2003) Kinetic differences between the isoforms of glutamate decarboxylase implications for the regulation of GABA synthesis. J Neurochem 86 879-887. 

Chattopadhyaya B, Di Cristo G, Wu CZ, Knott G, Kuhlman S, Fu Y, PalmiterRD, Huang ZJ (2007) GAD67-mediated GABA synthesis and signaling regulate inhibitory synaptic innervation in the visual cortex. Neuron 54 889-903. 

Wu H, Jin Y, Buddhala C, Osterhaus G, Cohen E, Jin H, Wei J, Davis K, Obata K, Wu JY (2007) Role of glutamate decarboxylase (GAD) isoform, GAD65, in GABA synthesis and transport into synaptic vesicles-Evidence from GAD65-knockout mice studies. Brain Res 1154 80-83. 

Stafford MM, Brown MN, Mishra P et al (2010) Glutamate spillover augments GABA synthesis and release from axodendritic synapses in rat hippocampus. Hippocampus 20 134-144... 

Mathews, G. C. and Diamond, J. S. 2003. Neuronal glutamate uptake contributes to GABA synthesis and inhibitory synaptic strength. J. Neurosci. 23 2040-48. 

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